Monovalent metal cation dry powders for inhalation

ABSTRACT

The present invention is directed toward respirable dry powders and particles for systemic delivery of pharmaceutically active agents or delivery to the respiratory tract. The dry powders contain one or more monovalent metal cations (such as Na+), are small and dispersible.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/387,883, filed on Sep. 29, 2010 and the benefit of U.S. ProvisionalApplication No. 61/481,879, filed on May 3, 2011, the entire teachingsof these applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Pulmonary delivery of therapeutic agents can offer several advantagesover other modes of delivery. These advantages include rapid onset ofdrug action, the convenience of patient self-administration, thepotential for reduced drug side-effects, ease of delivery, theelimination of needles, and the like. With these advantages, inhalationtherapy is capable of providing a drug delivery system that is easy touse in an inpatient or outpatient setting.

Metered dose inhalers (MDIs) are used to deliver therapeutic agents tothe respiratory tract. MDIs are generally suitable for administeringtherapeutic agents that can be formulated as solid respirable dryparticles in a volatile liquid under pressure. Opening of a valvereleases the suspension at relatively high velocity. The liquid thenvolatilizes, leaving behind a fast-moving aerosol of dry particles thatcontain the therapeutic agent. MDIs are reliable for drug delivery tothe upper and middle airways but are limited because they typicallydeliver only low doses per actuation. However, it is the bronchioles andalveoli that are often the site of manifestation of pulmonary diseasessuch as asthma and respiratory infections.

Liquid aerosol delivery is one of the oldest forms of pulmonary drugdelivery. Typically, liquid aerosols are created by an air jetnebulizer, which releases compressed air from a small orifice at highvelocity, resulting in low pressure at the exit region due to theBernoulli effect. See, e.g., U.S. Pat. No. 5,511,726. The low pressureis used to draw the fluid to be aerosolized out of a second tube. Thisfluid breaks into small droplets as it accelerates in the air stream.Disadvantages of this standard nebulizer design include relatively largeprimary liquid aerosol droplet size often requiring impaction of theprimary droplet onto a baffle to generate secondary splash droplets ofrespirable sizes, lack of liquid aerosol droplet size uniformity,significant recirculation of the bulk drug solution, and low densitiesof small respirable liquid aerosol droplets in the inhaled air.

Ultrasonic nebulizers use flat or concave piezoelectric disks submergedbelow a liquid reservoir to resonate the surface of the liquidreservoir, forming a liquid cone which sheds aerosol particles from itssurface (U.S. 2006/0249144 and U.S. Pat. No. 5,551,416). Since noairflow is required in the aerosolization process, high aerosolconcentrations can be achieved, however the piezoelectric components arerelatively expensive to produce and are inefficient at aerosolizingsuspensions, requiring active drug to be dissolved at low concentrationsin water or saline solutions. Newer liquid aerosol technologies involvegenerating smaller and more uniform liquid respirable dry particles bypassing the liquid to be aerosolized through micron-sized holes. See,e.g., U.S. Pat. No. 6,131,570; U.S. Pat. No. 5,724,957; and U.S. Pat.No. 6,098,620. Disadvantages of this technique include relativelyexpensive piezoelectric and fine mesh components as well as fouling ofthe holes from residual salts and from solid suspensions.

Dry powder inhalation has historically relied on lactose blending toallow for the dosing of particles that are small enough to be inhaled,but aren't dispersible enough on their own. This process is known to beinefficient and to not work for some drugs. For example, the drugloading in the overall dry powder is low due to the presence of thelactose carrier which is typically large and bulky. Several groups havetried to improve on these shortcomings by developing dry powder inhaler(DPI) formulations that are respirable and dispersible and thus do notrequire lactose blending. Dry powder formulations for inhalation therapyare described in U.S. Pat. No. 5,993,805 to Sutton et al.; U.S. Pat. No.6,921,6527 to Platz et al.; WO 0000176 to Robinson et al.; WO 9916419 toTarara et al.; WO 0000215 to Bot et al; U.S. Pat. No. 5,855,913 to Haneset al.; and U.S. Pat. Nos. 6,136,295 and 5,874,064 to Edwards et al.

Broad clinical application of dry powder inhalation delivery has beenlimited by difficulties in generating dry powders of appropriateparticle size, particle density, and dispersibility, in keeping the drypowder stored in a dry state, and in developing a convenient, hand-helddevice that effectively disperses the respirable dry particles to beinhaled in air. In addition, the particle size of dry powders forinhalation delivery is inherently limited by the fact that smallerrespirable dry particles are harder to disperse in air. Dry powderformulations, while offering advantages over cumbersome liquid dosageforms and propellant-driven formulations, are prone to aggregation andlow flowability which considerably diminish dispersibility and theefficiency of dry powder-based inhalation therapies. For example,interparticular Van der Waals interactions and capillary condensationeffects are known to contribute to aggregation of dry particles. Hickey,A. et al., “Factors Influencing the Dispersion of Dry Powders asAerosols”, Pharmaceutical Technology, August, 1994.

The propensity for particles to aggregate or agglomerate increases asparticle size decreases. In order to deaggregate particles of a smallersize, a relatively larger dispersion energy is needed. This can bedescribed as inhaled flowrate dependency since the degree of dispersionof the agglomerated particles is a function of inhaled flowrate. Whatthis means to a clinician and a patient is that the dose the patientreceives varies depending on their inspiratory flowrate.

One example of how the art has dealt with the need for a high dispersionenergy is to require the patient to inhale on a passive dry powderinhaler (DPI) at a high inspiratory flow rate. In Anderson, et al.European Respiratory Journal, 1997, November; 10(11):2465-73, micronizedsodium chloride was delivered to patients to cause broncho-provocation.Patients were required to breathe forcefully on the DPI in order toreceive the broncho-provocative dose. Flowrates of greater than or equalto 50 LPM on a standard DPI and greater than 28 LPM on a high-resistanceDPI were required, both produce higher dispersion energies.

Requiring a patient to inspire at a high flowrate is not alwayspossible, or predictable, e.g., due to patient's disease state orphysical condition. Previously, the problem of delivering active agentsto the respiratory tract at a relatively constant dose across variousflowrates was addressed i) by adding large carrier particle (e.g.,typically with an average particle size in excess of 40 μm), such aslactose, ii) by manufacturing particles that are large and porous (e.g.,tap density of less than 0.4 g/cc), or iii) by using active dry powderdevices that apply significant force to disperse the powders. The firstmethod is still subject to significant variability at varyinginspiratory flowrates. The second method requires large volumes ofpowder to deliver a relatively large dose of powder. The third methodrequires an expensive inhaler to be purchased, that may also be subjectto technical failure.

To overcome interparticle adhesive forces, Batycky et al. in U.S. Pat.No. 7,182,961 teach production of so called “aerodynamically lightrespirable particles,” which have a volume median geometric diameter(VMGD) of greater than 5 microns (μm) as measured using a laserdiffraction instrument such as HELOS (manufactured by Sympatec,Princeton, N.J.) and a tap density of less than 0.4 g/cc. See Batycky etal., column 4, lines 21-45, and column 7, lines 42-65.

Similar to Batycky, et al., Lipp et al., in U.S. Pat. No. 7,807,200teach production of “aerodynamically light respirable particles” thatpossess a tap density of less than 0.4 g/cc. See Lipp et al., column 4,line 65 to column 5, line 47 where the use of a carboxylate moiety,e.g., citric acid and sodium citrate, a multivalent salt, e.g., adivalent salt, and a phospholipid, e.g., a phospholipid that isendogenous to the lung is taught. Due to the presence of the threecomponents, as well as porous nature of the particle, as indicated by atap density which is less than 0.4 g/cc, the formulations in Lipp et al.would be difficult to prepare with a high loading of active agents.

Another approach to improve dispersibility of respirable particles ofaverage particle size of less than 10 μm, involves the addition of awater soluble polypeptide or addition of suitable excipients (includingamino acid excipients such as leucine) in an amount of 50% to 99.9% byweight of the total composition. Eljamal et al., U.S. Pat. No.6,582,729, column 4, lines 12-19 and column 5, line 55 to column 6, line31. However, this approach reduces the amount of active agent that canbe delivered using a fixed amount of powder. Therefore, an increasedamount of dry powder is required to achieve the intended therapeuticresults, for example, multiple inhalations and/or frequentadministration may be required. Still other approaches involve the useof devices that apply mechanical forces, such as pressure fromcompressed gasses, to the small particles to disrupt interparticularadhesion during or just prior to administration. See, e.g., U.S. Pat.Nos. 7,601,336 to Lewis et al., 6,737,044 to Dickinson et al., 6,546,928to Ashurst et al., or U.S. Pat. Applications 20090208582 to Johnston etal.

A further limitation that is shared by each of the above methods is thatthe aerosols produced typically include substantial quantities of inertcarriers, solvents, emulsifiers, propellants, and other non-drugmaterial. In general, large quantities of non-drug material are requiredfor effective formation of respirable dry particles small enough foralveolar delivery (e.g. less than 5 microns and preferably less than 3microns). However, these amounts of non-drug material also serve toreduce the purity and amount of active drug substance that can bedelivered. Thus, these methods remain substantially incapable ofintroducing large active drug dosages accurately to a patient forsystemic delivery.

Therefore, there remains a need for the formation of small particle sizeaerosols that are highly dispersible. In addition, methods that produceaerosols comprising greater quantities of drug and lesser quantities ofnon-drug material are needed. Finally, a method that allows a patient toadminister a unit dosage rapidly with one or two, small volume breathsis needed.

SUMMARY OF THE INVENTION

The invention relates to respirable dry particles that contain one ormore monovalent metal cations (such as Na⁺) and to dry powders thatcontain the respirable particles. In particular, aspects of theinvention relate to respirable dry powders that contain respirable dryparticles that comprise a monovalent metal cation salt in an amount ofat least about 3% by weight of the dry particle; the respirable dryparticles have a volume median geometric diameter (VMGD) of about 10microns or less and a dispersibility ratio (1/4 bar) of less than about2 as measured by laser diffraction (RODOS/HELOS system). Respirable dryparticles that consist of 10% leucine and 90% NaCl; or 60% leucine and40% NaCl; and respirable dry particles that contain a divalent metalcation in an amount of 3% or more by weight of the dry particle are notincluded in the invention. Preferably, the respirable dry particles havea volume median geometric diameter (VMGD) of about 5.0 microns or less.

The respirable dry powder can have a dispersibility ratio (1/4 bar) ofless than about 1.5 as measured at the 1 bar and 4 bar dispersionsettings on the HELOS/RODOS laser diffraction system. The respirable drypowder can have a Fine Particle Fraction (FPF) of less than 5.6 micronsof at least 45% and/or a Fine Particle Fraction (FPF) of less than 3.4microns of at least 30%, and/or a Fine Particle Fraction (FPF) of lessthan 5.0 microns of at least 45%. The respirable dry powder can have amass median aerodynamic diameter (MMAD) of about 5 microns or less.

The monovalent metal cation salt present in the respirable dry particlescan have a solubility of ≧0.5 g/L in water or ≧400 g/L in water at 25°C., 1 bar. In some embodiments, the monovalent metal salt is selectedfrom the group consisting of a sodium salt, a potassium salt, a lithiumsalt, and combinations thereof. Preferred salts include sodium chloride,sodium lactate, sodium citrate, sodium sulfate or combinations thereof.Other preferred salts include potassium chloride, potassium citrate andcombinations thereof.

The respirable dry powder can further comprise at least onepharmaceutically acceptable excipient. The excipient can be present inany desired amount. In some embodiments, the excipient is selected fromthe group consisting of leucine, maltodextrin, mannitol and combinationsthereof.

The respirable dry powder can have a tap density of greater than 0.4g/cc, greater than 0.5 g/cc or greater than 0.6 g/cc.

If desired, the respirable dry powder can comprise a pharmaceuticallyactive agent. The pharmaceutically active agent can be a component ofthe respirable dry particles, or can be blended with the respirable dryparticles. In some embodiments, the pharmaceutically active agent is anantibiotic, a LABA, a LAMA, a corticosteroid, or any combinationthereof. In other embodiments, the pharmaceutically active agent is amacromolecule. For example, the macromolecule can be a cytokine,chemokine, growth factor, hormone or antibody.

Aspects of the invention also relate to a method for treating arespiratory disease comprising administering to the respiratory tract ofa patient in need thereof an effective amount of a respirable dry powderas described herein.

Aspects of the invention also relate to a method for treating orpreventing an acute exacerbation of a respiratory disease comprisingadministering to the respiratory tract of a patient in need thereof aneffective amount of a respirable dry powder as described herein.

Aspects of the invention also relate to a method for treating orpreventing an infectious disease of the respiratory tract comprisingadministering to the respiratory tract of a patient in need thereof aneffective amount of a respirable dry powder as described herein.

Aspects of the invention also relate to a dry powder as described hereinfor use in therapy and for the treatment or prevention of a disease asdescribed herein.

Described herein are respirable dry particles that contain one or moremonovalent metal cations (such as Na⁺ or K⁺) and dry powders thatcontain the respirable particles. In particular, aspects of theinvention relate to respirable dry powders that contain respirable dryparticles that comprise a monovalent metal cation salt in an amount ofat least about 3% by weight of the dry particle. The respirable dryparticles and respirable dry powders can further contain apharmaceutically active agent (e.g. therapeutic and/or prophylacticagent). For example, one or more active agents are co-formulated (e.g.,co-spray dried, co-freeze-dried, processed via super-criticalfluid-based technologies, etc.) with the one or more monovalent salt(s)and optionally one or more excipient(s) to make respirable dryparticles. In another example, the respirable dry powders are comprisedof respirable dry particles containing the one or more monovalent metalcations, and can be used as carrier particles to deliver one or morepharmaceutically active agents (e.g., as a blend of the respirable dryparticles and the one or more pharmaceutically active agents). In afurther example, one or more active agents are co-formulated with theone or more monovalent salts to make respirable dry particles. Theseco-formulated respirable dry particles (comprising a first, second, etc.active agent) can be used as such, or as carrier particles, to deliverone or more additional active agents (a second, third, fourth, etc.active agent). The additional active agent(s) may be, for example, inmicronized form. The one or more additional active agent(s) can be thesame active agent(s) that are co-formulated in the dry particle,different active agent(s), or a combination thereof.

Suitable active agents include, but are not limited to, mucoactive ormucolytic agents, surfactants, antibiotics, antivirals, antihistamines,cough suppressants, bronchodilators, anti-inflammatory agents, steroids,vaccines, adjuvants, expectorants, macromolecules, or therapeutics thatare helpful for chronic maintenance of cystic fibrosis (CF). Preferredactive agents include, but are not limited to, LABAs (e.g., formoterol,salmeterol), short-acting beta agonists (e.g., albuterol),corticosteroids (e.g., fluticasone), LAMAs (e.g., tiotropium),antibiotics (e.g., levofloxacin, tobramycin), antibodies (e.g.,therapeutic antibodies), hormones (e.g. insulin), cytokines, chemokines,growth factors, and combinations thereof. When the dry powders areintended for treatment of CF, preferred additional active agents areshort-acting beta agonists (e.g., albuterol), antibiotics (e.g.,levofloxacin), recombinant human deoxyribonuclease I (e.g., dornasealfa, also known as DNase), sodium channel blockers (e.g., amiloride),and combinations thereof.

The respirable dry particles of the invention are generally small anddispersible, and can be used to administer pharmaceutically active agentto the lungs, including the deep lung, for local action in the lungand/or for absorption through the lung for systemic action. Therespirable dry particles can also be large and dispersible.

In certain embodiments, the respirable dry powders and dry particlesdescribed herein are small and highly dispersible, and have otherproperties that enable them to be delivered to the respiratory tract,including the upper airway and the deep lung upon inhalation, such ashigh dispersibility, flowrate independence and/or minimizedoropharyngeal deposition. Accordingly, the dry powders and dry particlesdescribed herein are suitable for delivery of pharmaceutically activeagents to the upper airway or deep lung for local or systemic activity.

In addition to being small and dispersible, the respirable dry particlesare generally monovalent metal cation (e.g., Na⁺ or K⁺) dense and/orpharmaceutically active agent dense. For example, the dry particles cancontain a high percentage of monovalent metal cation salt (i.e., bedense in monovalent metal cation salt) and/or contain monovalent metalcation salts that dissociate to release two or more moles of monovalentmetal cation per mole of salt. Alternatively, or in addition, the dryparticles can contain a high percentage of one or more pharmaceuticallyactive agents. Accordingly, in some aspects, the respirable dryparticles of the invention may be monovalent metal cation salt (e.g., asodium salt or a potassium salt) and/or active agent dense and are smalland dispersible.

In another aspect, the respirable dry particles are mass dense (e.g.have a tap density or envelope mass density of greater than about 0.4g/cc, or at least about 0.45 g/cc or greater, about 0.5 g/cc or greater,about 0.55 g/cc or greater, about 0.6 g/cc or greater, about 0.7 g/cc orgreater or about 0.8 g/cc or greater), small, and dispersible.

The respirable dry particles are generally small, e.g., they possess ageometric diameter (VMGD) of less than about 10 microns, between 0.5microns and 10 microns, between 1 micron and 7 microns or between 1micron and 5 microns. Optionally, the MMAD of the dry powder may be lessthan 10 microns, less than 5 microns, between 0.5 and 10 microns, morepreferably between 1 and 5 microns, more preferably between 1 and 3microns or between 3 and 5 microns. The particles optionally have a tapdensity or envelope mass density greater than 0.4 g/cc, greater than0.45 g/cc, greater than 0.55 g/cc, between 0.45 g/cc and 1.2 g/cc, orbetween 0.55 g/cc and 1.0 g/cc. They are also generally dispersible.

The respirable dry particles may also be large, e.g., they may possess aVMGD between 10 microns and 30 microns, or between 10 microns and 20microns. Optionally, the MMAD of the dry powder may be between 0.5 and10 microns, more preferably between 1 and 5 microns. The particlesoptionally have a tap density or envelope mass density between 0.01 g/ccand 0.4 g/cc, or between 0.05 g/cc and 0.25 g/cc. They are alsogenerally dispersible.

Respirable dry powders that contain small particles and that aredispersible in air, and preferably dense (e.g., dense in monovalentmetal cation and/or pharmaceutically active agent) are a departure fromthe conventional wisdom. It is well known that the propensity forparticles to aggregate or agglomerate increases as particle sizedecreases. See, e.g., Hickey, A. et al., “Factors Influencing theDispersion of Dry Powders as Aerosols”, Pharmaceutical Technology,August, 1994.

Respirable dry powder and dry particles described herein that are small,dispersible and dense (e.g., dense in monovalent metal cations (e.g.,sodium containing salt(s)), active agent) and/or mass dense) provideadvantages for administration and/or therapeutic uses. For example, adesired therapeutically effective dose of an active agent can bedelivered when a subject inhales a small volume of dry powder.Accordingly, in comparison to conventional dry powders, such as powdersthat contain lactose carrier particles a smaller amount of powder willneed to be administered in order to deliver the desired dose ofpharmaceutically active agent. For example, the desired dose can bedelivered with one or two inhalations from a capsule-type orblister-type inhaler.

In certain embodiments, provided herein are respirable dry powders thatcontain respirable particles that are small and dispersible in airwithout the need for additional energy sources beyond the subject'sinhalation. Thus, the respirable dry powders and respirable dryparticles can be used to deliver active agents to the respiratory tract,without including large amounts of non-active components (e.g.,excipients such as lactose carrier particles) in the particles orpowders, or by using devices that apply mechanical forces to disruptaggregated or agglomerated particles during or just prior toadministration. For example, devices such as passive dry powder inhalersmay be used to deliver a dry powder comprised of one or more monovalentcation salts and one or more active agents described herein. In someembodiments, the respirable dry powders and respirable dry particles donot include any excipient (e.g., leucine) in the particles or powders.

Provided herein, in certain embodiments, are respirable dry particlesthat contain one or more divalent metal cation salts, such as magnesiumor calcium-containing salts, where the divalent metal cation is presentin an amount of less than 3% by weight.

In one aspect, the respirable particles are not only small and highlydispersible, but can contain a large amount of active agent, e.g., 5% ormore, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more,60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 97%or more by weight of the dry particle. When an excipient is included inthe respirable dry powder or particles, the excipient may compriseabout, 50% or less by weight, about 40% or less by weight, about 30% orless by weight, about 20% or less by weight, about 12% or less byweight, about 10% or less by weight, about 8% or less by weight, about5% or less by weight, about 3% or less by weight, about 2% or less byweight or about 1% or less by weight).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E are graphs illustrating the aerodynamic particle sizedistribution of exemplary dry powders of the invention as measured by aneight stage Andersen Cascade Impactor (ACI). The graphs indicate thatall five dry powders were of a respirable size.

FIGS. 2A and 2B are graphs illustrating the efficacy of a monovalentcation-based dry powder formulation of FP/SX (fluticasonepropionate/salmeterol xinafoate) in reducing total cell (FIG. 2B) andeosinophil cell (FIG. 2B) counts in a ovalbumin (OVA) mouse model ofallergic asthma. The graphs indicate that the spray dried drug (FP/SX)remained effective in treating inflammation.

FIGS. 3A-3C are graphs illustrating the efficacy of a monovalentcation-based dry powder formulation of FP/SX in reducing total cell(FIG. 3A) and eosinophil cell (FIG. 3B) counts and airwayhyperreactivity (FIG. 3C) in an ovalbumin mouse model of allergicasthma. The graphs indicate that the spray dried drug (FP/SX) remainedeffective in treating both inflammation and airway hyperreactivity.

FIG. 4 is a graph illustrating the efficacy of a monovalent cation-baseddry powder formulation of FP/SX in reducing airway hyperreactivity in anovalbumin mouse model of allergic asthma. The graph indicates that thespray dried drug (FP/SX) remained effective in treating airwayhyperreactivity.

FIG. 5 is a graph illustrating the efficacy of a monovalent cation-baseddry powder formulation of tiotroprium bromide (TioB) in reducing airwayhyperreactivity in an ovalbumin mouse model of allergic asthma. Thegraph indicates that the spray dried drug (TioB) remained effective intreating airway hyperreactivity.

FIGS. 6A-6C are graphs illustrating the efficacy of a monovalentcation-based dry powder formulation of FP/SX in reducing total cell(FIG. 6A) and eosinophil cell (FIG. 6B) counts and airwayhyperreactivity (FIG. 6C) in a house dust mite (HDM) mouse model ofallergic asthma. The graphs indicate that the spray dried drug (FP/SX)remained effective in treating both inflammation and airwayhyperreactivity.

FIG. 7 is a graph illustrating the efficacy of a monovalent cation-baseddry powder formulation of ciprofloxacin (Formulation IV) in treatingbacterial pneumonia in vivo in a mouse model. The graph indicates thatspray dried ciproflaxacin was active against P. aeruginosa.

FIGS. 8 and 9 are graphs illustrating the efficacy of monovalentcation-based dry powder formulations of insulin at a loading of 8% and5%, respectively, at reducing the blood glucose levels in mice.

FIGS. 10A and 10B are graphs illustrating the ability of a monovalentcation-powder formulation of immunoglobulin G (IgG) to deliver IgG toboth the lungs and serum of mice. These graphs indicate that delivery ofa large protein to the lungs with a spray dried formulation of theprotein and a monovalent cation salt is feasible.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to respirable dry particles that contain one ormore monovalent metal cations (such as Na⁺) and to dry powders thatcontain the respirable particles. The dry particles can further containa pharmaceutically active agent, or can be used as carrier particles todeliver a pharmaceutically active agent. The respirable dry particles ofthe invention are generally small and dispersible, and can be used toadminister pharmaceutically active agent to the lungs, including thedeep lung, for local action in the lung or for absorption through thelung for systemic action.

In addition to being small and dispersible, the respirable dry particlesare generally monovalent metal cation (e.g., Na⁺) dense and/orpharmaceutically active agent dense. Respirable dry powders that containsmall particles and that are dispersible in air, and preferably dense(e.g., dense in monovalent metal cation and/or pharmaceutically activeagent) are a departure from the conventional wisdom. It is well knownthat the propensity for particles to aggregate or agglomerate increasesas particle size decreases. See, e.g., Hickey, A. et al., “FactorsInfluencing the Dispersion of Dry Powders as Aerosols”, PharmaceuticalTechnology, August, 1994.

Provided herein are respirable dry powders that contain respirableparticles that are small and dispersible in air without additionalenergy sources beyond the subject's inhalation. Thus, the respirable drypowders and respirable dry particles can be used to deliver activeagents to the respiratory tract, without including large amounts ofnon-active components (e.g., excipients such as lactose carrierparticles) in the particles or powders, or by using devices that applymechanical forces to disrupt aggregated or agglomerated particles duringor just prior to administration.

The respirable dry powders and respirable particles of the invention canbe dense in monovalent metal cations (e.g., sodium containing salt(s))and/or active agent). Thus, in one aspect, the respirable particles arenot only small and highly dispersible, but can contain a large amount ofmonovalent metal cation and/or pharmaceutically active agent.Accordingly, a smaller amount of powder will need to be administered inorder to deliver the desired dose of pharmaceutically active agent, incomparison to conventional dry powders, such as powders that containlactose carrier particles. For example, the desired dose can bedelivered with one or two inhalations from a capsule-type orblister-type inhaler.

The respirable dry powders and dry particles described herein are smalland highly dispersible, and have other properties that enable them to bedelivered to the respiratory tract, including the upper airway and thedeep lung upon inhalation, such as high dispersibility, flowrateindependence and minimized oropharyngeal deposition. Accordingly, thedry powders and dry particles described herein are suitable fordelivering pharmaceutically active agents to the upper airway or deeplung for local or systemic activity.

DEFINITIONS

The term “dry powder” as used herein refers to a composition thatcontains finely dispersed respirable dry particles that are capable ofbeing dispersed in an inhalation device and subsequently inhaled by asubject. Such a dry powder may contain up to about 25%, up to about 20%,or up to about 15% water or other solvent, or be substantially free ofwater or other solvent, or be anhydrous.

The term “dry particles” as used herein refers to respirable particlesthat may contain up to about 25%, up to about 20%, or up to about 15%water or other solvent, or be substantially free of water or othersolvent, or be anhydrous.

The term “respirable” as used herein refers to dry particles or drypowders that are suitable for delivery to the respiratory tract (e.g.,pulmonary delivery) in a subject by inhalation. Respirable dry powdersor dry particles have a mass median aerodynamic diameter (MMAD) of lessthan about 10 microns, preferably about 5 microns or less.

The term “small” as used herein to describe respirable dry particlesrefers to particles that have a volume median geometric diameter (VMGD)of about 10 microns or less, preferably about 5 microns or less. VMGDmay also be called the volume median diameter (VMD), x50, or Dv50.

As used herein, the terms “administration” or “administering” ofrespirable dry particles refers to introducing respirable dry particlesto the respiratory tract of a subject.

As used herein, the term “respiratory tract” includes the upperrespiratory tract (e.g., nasal passages, nasal cavity, throat, andpharynx), respiratory airways (e.g., larynx, trachea, bronchi, andbronchioles) and lungs (e.g., respiratory bronchioles, alveolar ducts,alveolar sacs, and alveoli).

The term “dispersible” is a term of art that describes thecharacteristic of a dry powder or dry particles to be dispelled into arespirable aerosol. Dispersibility of a dry powder or dry particles isexpressed herein as the quotient of the volume median geometric diameter(VMGD) measured at a dispersion (i.e., regulator) pressure of 1 bardivided by the VMGD measured at a dispersion (i.e., regulator) pressureof 4 bar, VMGD at 0.5 bar divided by the VMGD at 4 bar as measured byHELOS/RODOS, VMGD at 0.2 bar divided by the VMGD at 2 bar as measured byHELOS/RODOS, or VMGD at 0.2 bar divided by the VMGD at 4 bar as measuredby HELOS/RODOS. These quotients are referred to herein as “1 bar/4 bar,”“0.5 bar/4 bar,” “0.2 bar/2 bar,” and “0.2 bar/4 bar,” respectively, anddispersibility correlates with a low quotient. For example, 1 bar/4 barrefers to the VMGD of respirable dry particles or powders emitted fromthe orifice of a RODOS dry powder disperser (or equivalent technique) atabout 1 bar, as measured by a HELOS or other laser diffraction system,divided the VMGD of the same respirable dry particles or powdersmeasured at 4 bar by HELOS/RODOS. Thus, a highly dispersible dry powderor dry particles will have a 1 bar/4 bar or 0.5 bar/4 bar ratio that isclose to 1.0. Highly dispersible powders have a low tendency toagglomerate, aggregate or clump together and/or, if agglomerated,aggregated or clumped together, are easily dispersed or de-agglomeratedas they emit from an inhaler and are breathed in by a subject.Dispersibility can also be assessed by measuring the size emitted froman inhaler as a function of flow rate. VMGD may also be called thevolume median diameter (VMD), x50, or Dv50.

The terms “FPF (<5.6),” “FPF (<5.6 microns),” and “fine particlefraction of less than 5.6 microns” as used herein, refer to the fractionof a sample of dry particles that have an aerodynamic diameter of lessthan 5.6 microns. For example, FPF (<5.6) can be determined by dividingthe mass of respirable dry particles deposited on the stage one and onthe collection filter of a two-stage collapsed Andersen Cascade Impactor(ACI) by the mass of respirable dry particles weighed into a capsule fordelivery to the instrument. This parameter may also be identified as“FPF_TD(<5.6),” where TD means total dose. A similar measurement can beconducted using an eight-stage ACI. The eight-stage ACI cutoffs aredifferent at the standard 60 L/min flow rate, but the FPF_TD(<5.6) canbe extrapolated from the eight-stage complete data set. The eight-stageACI result can also be calculated by the USP method of using the dosecollected in the ACI instead of what was in the capsule to determineFPF.

The terms “FPF (<5.0)”, “FPF<5 μm”, “FPF (<5.0 microns),” and “fineparticle fraction of less than 5.0 microns” as used herein, refer to thefraction of a mass of respirable dry particles that have an aerodynamicdiameter of less than 5.0 micrometers. For example, FPF (<5.0) can bedetermined by using an eight-stage ACI at the standard 60 L/min flowrate by extrapolating from the eight-stage complete data set. Thisparameter may also be identified as “FPF_TD(<5.0),” where TD means totaldose. When used in conjunction with a geometric size distribution suchas those given by a Malvern Spraytec, Malvern Mastersizer or SympatecHELOS particle sizer, “FPF (<5.0)” refers to the fraction of a mass ofrespirable dry particles that have a geometric diameter of less than 5.0micrometers.

The terms “FPD(<4.4)”, ‘FPD<4.4 μm”, FPD(<4.4 microns)” and “fineparticle dose of less than 4.4 microns” as used herein, refer to themass of respirable dry powder particles that have an aerodynamicdiameter of less than 4.4 micrometers. For example, FPD<4.4 μm can bedetermined by using an eight-stage ACI at the standard 60 L/min flowrateand summing the mass deposited on the filter, and stages 6, 5, 4, 3, and2 for a single dose of powder actuated into the ACI.

The terms “FPF (<3.4),” “FPF (<3.4 microns),” and “fine particlefraction of less than 3.4 microns” as used herein, refer to the fractionof a mass of respirable dry particles that have an aerodynamic diameterof less than 3.4 microns. For example, FPF (<3.4) can be determined bydividing the mass of respirable dry particles deposited on thecollection filter of a two-stage collapsed ACI by the total mass ofrespirable dry particles weighed into a capsule for delivery to theinstrument. This parameter may also be identified as “FPF_TD(<3.4),”where TD means total dose. A similar measurement can be conducted usingan eight-stage ACI. The eight-stage ACI result can also be calculated bythe USP method of using the dose collected in the ACI instead of whatwas in the capsule to determine FPF.

The terms “FPF (<5.0),” “FPF (<5.0 microns),” and “fine particlefraction of less than 5.0 microns” as used herein, refer to the fractionof a mass of respirable dry particles that have an aerodynamic diameterof less than 5.0 microns. For example, FPF (<5.0) can be determined byusing an eight-stage ACI at the standard 60 L/min flow rate byextrapolating from the eight-stage complete data set. This parameter mayalso be identified as “FPF_TD(<5.0),” where TD means total dose.

As used herein, the term “emitted dose” or “ED” refers to an indicationof the delivery of a drug formulation from a suitable inhaler deviceafter a firing or dispersion event. More specifically, for dry powderformulations, the ED is a measure of the percentage of powder that isdrawn out of a unit dose package and that exits the mouthpiece of aninhaler device. The ED is defined as the ratio of the dose delivered byan inhaler device to the nominal dose (i.e., the mass of powder per unitdose placed into a suitable inhaler device prior to firing). The ED isan experimentally-measured parameter, and can be determined using themethod of USP Section 601 Aerosols, Metered-Dose Inhalers and Dry PowderInhalers, Delivered-Dose Uniformity, Sampling the Delivered Dose fromDry Powder Inhalers, United States Pharmacopeia convention, Rockville,Md., 13^(th) Revision, 222-225, 2007. This method utilizes an in vitrodevice set up to mimic patient dosing.

The term “capsule emitted powder mass” or “CEPM” as used herein, refersto the amount of dry powder formulation emitted from a capsule or doseunit container during an inhalation maneuver. CEPM is measuredgravimetrically, typically by weighing a capsule before and after theinhalation maneuver to determine the mass of powder formulation removed.CEPM can be expressed either as the mass of powder removed, inmilligrams, or as a percentage of the initial filled powder mass in thecapsule prior to the inhalation maneuver.

The term “effective amount,” as used herein, refers to the amount ofactive agent needed to achieve the desired therapeutic or prophylacticeffect, such as an amount that is sufficient to reduce pathogen (e.g.,bacteria, virus) burden, reduce symptoms (e.g., fever, coughing,sneezing, nasal discharge, diarrhea and the like), reduce occurrence ofinfection, reduce viral replication, or improve or prevent deteriorationof respiratory function (e.g., improve forced expiratory volume in 1second FEV₁ and/or forced expiratory volume in 1 second FEV₁ as aproportion of forced vital capacity FEV₁/FVC, reducebronchoconstriction), produce an effective serum concentration of apharmaceutically active agent, increase mucociliary clearance, reducetotal inflammatory cell count, or modulate the profile of inflammatorycell counts. The actual effective amount for a particular use can varyaccording to the particular dry powder or dry particle, the mode ofadministration, and the age, weight, general health of the subject, andseverity of the symptoms or condition being treated. Suitable amounts ofdry powders and dry particles to be administered, and dosage schedulesfor a particular patient can be determined by a clinician of ordinaryskill based on these and other considerations.

The term “pharmaceutically acceptable excipient” as used herein meansthat the excipient can be taken into the lungs with no significantadverse toxicological effects on the lungs. Such excipients aregenerally regarded as safe (GRAS) by the U.S. Food and DrugAdministration.

All references to salts (e.g., sodium containing salts) herein includeanhydrous forms and all hydrated forms of the salt.

All weight percentages are given on a dry basis.

Dry Powders and Dry Particles

Aspects of the invention relate to respirable dry powders and dryparticles that contain one or more monovalent metal cation salts,preferably one or more sodium salts and/or potassium salts.

Chemical Composition

In one aspect, the respirable dry particles of the invention contain oneor more monovalent metal cation salts, such as a sodium salt, apotassium salt and/or a lithium salt, but do not contain apharmaceutically active agent. These types of respirable dry particlescan be used as carrier particles to deliver a pharmaceutically activeagent to the respiratory tract (e.g., lungs) for local or systemicdelivery. For example, this type of respirable dry particle can beblended with a pharmaceutically active agent, for example in the form ofa micronized powder, to produce a dry powder of the invention.

In another aspect, the respirable dry particles of the invention containone or more monovalent metal cation salts, such as a sodium salt and/ora potassium salt, and further contain a pharmaceutically active agent.These types of respirable dry particles can be prepared, for example, byspray drying a feed stock that contains the monovalent metal cationsalt, the pharmaceutically active agent and optionally an excipient, asdescribed herein. This type of dry particle can be used to deliver apharmaceutically active agent to the respiratory tract (e.g., lungs) forlocal or systemic delivery.

In a further aspect, the respirable dry particles contain one or moremonovalent metal cation salts and one or more active agents. These dryparticles can be combined, additionally, with one or more active agents,e.g., by blending, to form a respirable dry powder.

The invention excludes respirable dry powders and respirable dryparticles that consist of 10% leucine and 90% NaCl; or 60% leucine and40% NaCl. The invention also excludes respirable dry powders andrespirable dry particles that contain a divalent metal cation (e.g., inthe form of a salt) in an amount of 3% or more or that contain adivalent metal cation salt in an amount of 5% or more. In someembodiments, the respirable dry powders and respirable dry particles donot include sodium chloride. In some embodiments, the respirable drypowders and respirable dry particles do not include sodium citrate orcitric acid. In some embodiments, the respirable dry powders andrespirable dry particles do not include potassium phosphate. In someembodiments, the respirable dry powders and respirable dry particles donot include potassium sulfate. In some embodiments, the respirable drypowders and respirable dry particles do not include a phospholipid as anexcipient. Some examples of phospholipids includedipalmitoylphosphatidylcholine (DPPC) and1.2-distearoyl-sn-glycero-3-phosphocholine (DSPC). In some embodiments,the respirable dry powders and respirable dry particles do not include asurfactant as an active agent. Some examples of surfactants includephospholipids such as dipalmitoylphosphatidylcholine (DPPC) and1.2-distearoyl-sn-glycero-3-phosphocholine (DSPC). In some embodiments,the respirable dry powders and respirable dry particles do not includelactose as an excipient. In some embodiments, the respirable dry powdersand respirable dry particles do not include leucine as an excipient. Insome embodiments, the respirable dry powders and respirable dryparticles do not include mannitol as an excipient. In some embodiments,the respirable dry powders and respirable dry particles do not include adivalent salt. Examples of divalent salts include a calcium salt and amagnesium salt.

Preferred monovalent metal salts (e.g., sodium salts, potassium salts)have one, or preferably two or more of the following characteristics:(i) can be processed into respirable dry powders, (ii) possesssufficient physicochemical stability in dry powder form to facilitatethe production of a powder that is dispersible and physically stableover a range of conditions, including upon exposure to elevatedhumidity, (iii) undergo rapid dissolution upon deposition in the lungs,for example, half of the mass of the cation of the monovalent metal saltcan be dissolved in less than 30 minutes, less than 15 minutes, lessthan 5 minutes, less than 2 minutes, less than 1 minute, or less than 30seconds, and (iv) do not possess properties that can result in poortolerability or adverse events, such as a significant exothermic orendothermic heat of solution (ΔH) for example, a ΔH lower than of about−10 kcal/mol or greater than about 10 kcal/mol. Rather, a preferred ΔHis between about −9 kcal/mol and about 9 kcal/mol, between about −8kcal/mol and about 8 kcal/mol, between about −7 kcal/mol and about 7kcal/mol, between about −6 kcal/mol and about 6 kcal/mol, between about−5 kcal/mol and about 5 kcal/mol, between about −4 kcal/mol and about 4kcal/mol, between about −3 kcal/mol and about 3 kcal/mol, between about−2 kcal/mol and about 2 kcal/mol, between about −1 kcal/mol and about 1kcal/mol, or about 0 kcal/mol.

Suitable sodium, potassium and lithium salts can have desired solubilitycharacteristics. In general, highly or moderately soluble sodium andpotassium salts are preferred. For example, sodium and potassium saltsthat are contained in the respirable dry particles and dry powders canhave a solubility in distilled water at room temperature (20-30° C.) and1 bar of at least about 0.4 g/L, at least about 0.85 g/L, at least about0.90 g/L, at least about 0.95 g/L, at least about 1.0 g/L, at leastabout 2.0 g/L, at least about 5.0 g/L, at least about 6.0 g/L, at leastabout 10.0 g/L, at least about 20 g/L, at least about 50 g/L, at leastabout 90 g/L, at least about 120 g/L, at least about 500 g/L, at leastabout 700 g/L or at least about 1000 g/L. Preferably, the sodium andpotassium salts have a solubility greater than about 0.90 g/L, greaterthan about 2.0 g/L, or greater than about 90 g/L. Alternatively, thesodium and potassium salts that are contained in the respirable dryparticles and dry powders can have a solubility in distilled water atroom temperature (20-30° C.) and 1 bar of between at least about 0.4 g/Lto about 200 g/L, between about 1.0 g/L to about 120 g/L, between 5.0g/L to about 50 g/L,

Suitable sodium salts that can be present in the respirable dryparticles of the invention include, for example, sodium chloride, sodiumcitrate, sodium sulfate, sodium lactate, sodium acetate, sodiumbicarbonate, sodium carbonate, sodium stearate, sodium ascorbate, sodiumbenzoate, sodium biphosphate, dibasic sodium phosphate, sodiumphosphate, sodium bisulfite, sodium borate, sodium gluconate, sodiummetasilicate, sodium propionate and the like. In a preferred aspect, thedry powders and dry particles include sodium chloride, sodium citrate,sodium lactate, sodium sulfate, or any combination of these salts. Inanother preferred aspect, the dry powders and dry particles includesodium lactate, sodium sulfate, or any combination of these salts. Inanother aspect, the dry powders and dry particles include sodiumacetate, sodium carbonate, sodium gluconate, or any combination of thesesalts.

Suitable potassium salts include, for example, potassium chloride,potassium citrate, potassium bromide, potassium iodide, potassiumbicarbonate, potassium nitrite, potassium persulfate, potassium sulfite,potassium sulfate, potassium bisulfite, potassium phosphate, potassiumacetate, potassium citrate, potassium glutamate, dipotassium guanylate,potassium gluconate, potassium malate, potassium ascorbate, potassiumsorbate, potassium succinate, potassium sodium tartrate and anycombination thereof. For example, the dry powders and dry particlesinclude potassium chloride, potassium citrate, potassium phosphare,potassium sulfate, or any combination of these salts. In a preferredaspect, the dry powders and dry particles include potassium chlorideand/or potassium citrate.

Suitable lithium salts include, for example, lithium chloride, lithiumbromide, lithium carbonate, lithium nitrate, lithium sulfate, lithiumacetate, lithium lactate, lithium citrate, lithium aspartate, lithiumgluconate, lithium malate, lithium ascorbate, lithium orotate, lithiumsuccinate or and combination thereof.

Dry powder and particles of the invention can contain a high percentageof sodium salt and/or potassium salt in the composition, and can besodium cation (Na⁺) and/or potassium cation (K⁺) dense. The dryparticles may contain 3% or more, 5% or more, 10% or more, 15% or more,20% ore more, 25% or more, 30% or more, 35% or more, 40% or more, 50% ormore, 60% or more, 70% or more, 75% or more, 80% or more, 85% or more,90% or more, or 95% or more sodium salt or potassium salt by weight.

Alternatively or in addition, the respirable dry particles of theinvention can contain a monovalent metal cation salt (e.g., sodium saltor potassium salt), which provides monovalent cation (e.g., Na⁺ or K⁺)in an amount of at least about 3% by weight of the respirable dryparticles. For example, the respirable dry particles of the inventioncan include a sodium salt or potassium salt which provides Na⁺ or K⁺, inan amount of at least about 5% by weight, at least about 7% by weight,at least about 10% by weight, at least about 11% by weight, at leastabout 12% by weight, at least about 13% by weight, at least about 14% byweight, at least about 15% by weight, at least about 17% by weight, atleast about 20% by weight, at least about 25% by weight, at least about30% by weight, at least about 35% by weight, at least about 40% byweight, at least about 45% by weight, at least about 50% by weight, atleast about 55% by weight, at least about 60% by weight, at least about65% by weight or at least about 70% by weight of the respirable dryparticles.

In some embodiments, the dry particles are small, dispersible, andpreferably dense in either monovalent metal cation (e.g., sodium,potassium), dense in monovalent metal cation salt (e.g. contain at leastabout 30% or at least about 40% (w/w) monovalent metal cation salt),and/or active agent dense. In a further aspect of the invention, the dryparticles are small, dispersible, and dense in mass (e.g. tap density,envelope mass density). In this last aspect, the particles can be densein monovalent metal cation salt (e.g. sodium, potassium), or can havelow loading of metal cation salt in the formulation.

If desired, the respirable dry particles of the invention contain one ormore other salts in addition to the sodium salt and/or potassium salt,such as one or more non-toxic salts of the elements magnesium, calcium,aluminum, silicon, scandium, titanium, vanadium, chromium, cobalt,nickel, copper, manganese, zinc, tin, silver and the like.

Suitable magnesium salts that can be present in the respirable dryparticles described herein include, for example, magnesium fluoride,magnesium chloride, magnesium bromide, magnesium iodide, magnesiumphosphate, magnesium sulfate, magnesium sulfite, magnesium carbonate,magnesium oxide, magnesium nitrate, magnesium borate, magnesium acetate,magnesium citrate, magnesium gluconate, magnesium maleate, magnesiumsuccinate, magnesium malate, magnesium taurate, magnesium orotate,magnesium glycinate, magnesium naphthenate, magnesium acetylacetonate,magnesium formate, magnesium hydroxide, magnesium stearate, magnesiumhexafluorsilicate, magnesium salicylate or any combination thereof. In apreferred aspect, the dry powder or dry particles include magnesiumsulfate, magnesium lactate, magnesium chloride, magnesium citrate, andmagnesium carbonate. Preferred magnesium salts are magnesium sulfate andmagnesium lactate.

Suitable calcium salts that can be present in the respirable dryparticles described herein include, for example, calcium chloride,calcium sulfate, calcium lactate, calcium citrate, calcium carbonate,calcium acetate, calcium phosphate, calcium alginate, calcium stearate,calcium sorbate, calcium gluconate and the like. In certain preferredaspects, the dry powder or dry particles of the invention do not containcalcium phosphate, calcium citrate, and/or calcium chloride.

When the respirable dry particles of the invention contain a divalentmetal cation salt, such as a calcium salt or magnesium salt, and amonovalent cation salt, the divalent cation, as a component of one ormore salts, is present in an amount of less than 5% by weight of dryparticle, less than 3% by weight of dry particle, between 0.01% to about2.9% by weight of dry particle, or between 0.1% to 2.9% by weight of dryparticle.

The respirable dry particles of the invention can contain one or moremonovalent metal cation salts (e.g., sodium salts and/or potassiumsalts) in a total amount of about 1% to about 20% by weight of therespirable dry particles, about 21% to about 60% by weight of therespirable dry particles, or about 61% to about 100% by weight of therespirable dry particles. For example, the respirable dry particles ofthe invention can include one or more of the monovalent metal cationsalts (e.g., sodium salts and/or potassium salts) in a total amount ofbetween about 1% and about 5%, about 5% and about 25%, about 5% andabout 15%, about 21% and about 50%, about 21% and about 40%, about 30%and about 40%, about 30% and about 50%, about 61% and about 99%, about61% and about 90%, about 70% and about 100%, about 70% and about 99%, orabout 80% and about 99% by weight of the respirable dry particles.

If desired, the respirable dry particles described herein can include aphysiologically or pharmaceutically acceptable excipient. For example, apharmaceutically-acceptable excipient includes any of the standardcarbohydrates, sugar alcohols, and amino acids that are known in the artto be useful excipients for inhalation therapy, either alone or in anydesired combination. These excipients are generally relativelyfree-flowing particulates, do not thicken or polymerize upon contactwith water, are toxicologically innocuous when inhaled as a dispersedpowder and do not significantly interact with the active agent in amanner that adversely affects the desired physiological action.Carbohydrate excipients that are useful in this regard include the mono-and polysaccharides. Representative monosaccharides include carbohydrateexcipients such as dextrose (anhydrous and the monohydrate; alsoreferred to as glucose and glucose monohydrate), galactose, mannitol,D-mannose, sorbose and the like. Representative disaccharides includelactose, maltose, sucrose, trehalose and the like. Representativetrisaccharides include raffinose and the like. Other carbohydrateexcipients include maltodextrin and cyclodextrins, such as2-hydroxypropyl-beta-cyclodextrin can be used as desired. Representativesugar alcohols include mannitol, sorbitol and the like.

Suitable amino acid excipients include any of the naturally occurringamino acids that form a powder under standard pharmaceutical processingtechniques and include the non-polar (hydrophobic) amino acids and polar(uncharged, positively charged and negatively charged) amino acids, suchamino acids are of pharmaceutical grade and are generally regarded assafe (GRAS) by the U.S. Food and Drug Administration. Representativeexamples of non-polar amino acids include alanine, isoleucine, leucine,methionine, phenylalanine, proline, tryptophan and valine.Representative examples of polar, uncharged amino acids includecysteine, glycine, glutamine, serine, threonine, and tyrosine.Representative examples of polar, positively charged amino acids includearginine, histidine and lysine. Representative examples of negativelycharged amino acids include aspartic acid and glutamic acid. These aminoacids can be in the D or L optical isomer form, or a mixture of the twoforms. These amino acids are generally available from commercial sourcesthat provide pharmaceutical-grade products such as the Aldrich ChemicalCompany, Inc., Milwaukee, Wis. or Sigma Chemical Company, St. Louis, Mo.

Preferred amino acid excipients, such as the hydrophobic amino acidleucine, in the D or L optical form, or a mixture of the two forms, andcan be present in the dry particles of the invention in an amount ofabout 99% or less by weight of respirable dry particles. For example,the respirable dry particles of the invention can contain the amino acidleucine in an amount of about 0.1% to about 10% by weight, 5% to about30% by weight, about 10% to about 20% by weight, about 5% to about 20%by weight, about 11% to about 50% by weight, about 15% to about 50% byweight, about 20% to about 50% by weight, about 30% to about 50% byweight, about 11% to about 40% by weight, about 11% to about 30% byweight, about 11% to about 20% by weight, about 20% to about 40% byweight, about 51% to about 99% by weight, about 60% to about 99% byweight, about 70% to about 99% by weight, about 80% to about 99% byweight, about 51% to about 90% by weight, about 51% to about 80% byweight, about 51% to about 70% by weight, about 60% to about 90% byweight, about 70% to about 90% by weight, about 45% or less by weight,about 40% or less by weight, about 35% or less by weight, about 30% orless by weight, about 25% or less by weight, about 20% or less byweight, about 18% or less by weight, about 16% or less by weight, about15% or less by weight, about 14% or less by weight, about 13% or less byweight, about 12% or less by weight, about 11% or less by weight, about10% or less by weight, about 9% or less by weight, about 8% or less byweight, about 7% or less by weight, about 6% or less by weight, about 5%or less by weight, about 4% or less by weight, about 3% or less byweight, about 2% or less by weight, or about 1% or less by weight.

Preferred carbohydrate excipients, such as maltodextrin and mannitol,can be present in the dry particles of the invention in an amount ofabout 99% or less by weight of respirable dry particles. For example,the respirable dry particles of the invention can contain maltodextrinin an amount of about 0.1% to about 10% by weight, 5% to about 30% byweight by weight, about 10% to about 20% by weight by weight, about 5%to about 20% by weight, about 11% to about 50% by weight, about 15% toabout 50% by weight, about 20% to about 50% by weight, about 30% toabout 50% by weight, about 11% to about 40% by weight, about 11% toabout 30% by weight, about 11% to about 20% by weight, about 20% toabout 40% by weight, about 51% to about 99% by weight, about 60% toabout 99% by weight, about 70% to about 99% by weight, about 80% toabout 99% by weight, about 51% to about 90% by weight, about 51% toabout 80% by weight, about 51% to about 70% by weight, about 60% toabout 90% by weight, about 70% to about 90% by weight, about 45% or lessby weight, about 40% or less by weight, about 35% or less by weight,about 30% or less by weight, about 25% or less by weight, about 20% orless by weight, about 18% or less by weight, about 16% or less byweight, about 15% or less by weight, about 14% or less by weight, about13% or less by weight, about 12% or less by weight, about 11% or less byweight, about 10% or less by weight, about 9% or less by weight, about8% or less by weight, about 7% or less by weight, about 6% or less byweight, about 5% or less by weight, about 4% or less by weight, about 3%or less by weight, about 2% or less by weight, or about 1% or less byweight.

In some preferred aspects, the dry particles contain an excipientselected from leucine, maltodextrin, mannitol and any combinationthereof. In particular embodiments, the excipient is leucine,maltodextrin, or mannitol.

Aspects of the invention include respirable dry powders that containrespirable dry particles that contain one or more monovalent metalcation salts, such as a sodium salt and/or a potassium salt, but do notcontain a pharmaceutically active agent, that are blended with apharmaceutically active agent in powder form (e.g., micronized). Theseparticles can be used as carrier particles. The respirable dry powdercan include any desired pharmaceutically active agent, such as any ofthe pharmaceutically active agents described herein.

Aspects of the invention include, respirable dry particles that containone or more monovalent metal cation salts, such as a sodium salt and/ora potassium salt, and further contain a pharmaceutically active agent,such as any of the pharmaceutically active agents described herein, in aco-formulation.

Suitable pharmaceutically active agents for use in the respirable drypowders and respirable dry particles include mucoactive or mucolyticagents, surfactants, antibiotics, antivirals, antihistamines, coughsuppressants, bronchodilators, anti-inflammatory agents, steroids,vaccines, adjuvants, expectorants, macromolecules, or therapeutics thatare helpful for chronic maintenance of cystic fibrosis (CF).

Preferred active agents include, but are not limited to, LABAs (e.g.,formoterol, salmeterol), short-acting beta agonists (e.g., albuterol),corticosteroids (e.g., fluticasone), LAMAs (e.g., tiotropium),antibiotics (e.g., levofloxacin, tobramycin), antibodies (e.g.,therapeutic antibodies), hormones (e.g. insulin), chemokines, cytokines,growth factors, and combinations thereof. When the dry powders areintended for treatment of CF, preferred additional active agents areshort-acting beta agonists (e.g., albuterol), antibiotics (e.g.,levofloxacin), recombinant human deoxyribonuclease I (e.g., dornasealfa, also known as DNase), sodium channel blockers (e.g., amiloride),and combinations thereof. In certain embodiments, the pharmaceuticallyactive agent(s) can be blended with the respirable dry particlesdescribed herein, or co-formulated (e.g., spray dried) as desired.

In some embodiments, the respirable dry particles and respirable drypowders can contain an agent that disrupts and/or disperses biofilms.Suitable examples of agents to promote disruption and/or dispersion ofbiofilms include specific amino acid stereoisomers, e.g., D-leucine,D-methionine, D-tyrosine, D-tryptophan, and the like. (Kolodkin-Gal, I.,D. Romero, et al. “D-amino acids trigger biofilm disassembly.” Science328(5978): 627-629.) For example, all or a portion of the leucine in thedry powders described herein which contain leucine can be D-leucine.

Examples of suitable mucoactive or mucolytic agents include MUC5AC andMUC5B mucins, DNase, N-acetylcysteine (NAC), cysteine, nacystelyn,dornase alfa, gelsolin, heparin, heparin sulfate, P2Y2 agonists (e.g.UTP, INS365), nedocromil sodium, hypertonic saline, and mannitol.

Suitable surfactants include L-alpha-phosphatidylcholine dipalmitoyl(“DPPC”), diphosphatidyl glycerol (DPPG),1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS),1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DSPC),1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE),1-palmitoyl-2-oleoylphosphatidylcholine (POPC), fatty alcohols,polyoxyethylene-9-lauryl ether, surface active fatty, acids, sorbitantrioleate (Span 85), glycocholate, surfactin, poloxomers, sorbitan fattyacid esters, tyloxapol, phospholipids, and alkylated sugars.

If desired, the respirable dry particles and respirable dry powders cancontain an antibiotic. The antibiotic can be suitable for treating anydesired bacterial infection. The respirable dry particles and respirabledry powders that contain an antibiotic can be used to reduce the spreadof infection, either within a patient or from patient to patient. Forexample, the respirable dry particles and respirable dry powders fortreating bacterial pneumonia or VAT, can further comprise an antibiotic,such as a macrolide (e.g., azithromycin, clarithromycin anderythromycin), a tetracycline (e.g., doxycycline, tigecycline), afluoroquinolone (e.g., gemifloxacin, levofloxacin, ciprofloxacin andmocifloxacin), a cephalosporin (e.g., ceftriaxone, defotaxime,ceftazidime, cefepime), a penicillin (e.g., amoxicillin, amoxicillinwith clavulanate, ampicillin, piperacillin, and ticarcillin) optionallywith a β-lactamase inhibitor (e.g., sulbactam, tazobactam and clavulanicacid), such as ampicillin-sulbactam, piperacillin-tazobactam andticarcillin with clavulanate, an aminoglycoside (e.g., amikacin,arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin,rhodostreptomycin, streptomycin, tobramycin, and apramycin), a penem orcarbapenem (e.g. doripenem, ertapenem, imipenem and meropenem), amonobactam (e.g., aztreonam), an oxazolidinone (e.g., linezolid),vancomycin, glycopeptide antibiotics (e.g. telavancin),tuberculosis-mycobacterium antibiotics and the like.

If desired, the respirable dry particles and respirable dry powders cancontain an agent for treating infections with mycobacteria, such asMycobacterium tuberculosis. Suitable agents for treating infections withmycobacteria (e.g., M. tuberculosis) include an aminoglycoside (e.g.capreomycin, kanamycin, streptomycin), a fluoroquinolone (e.g.ciprofloxacin, levofloxacin, moxifloxacin), isozianid and isozianidanalogs (e.g. ethionamide), aminosalicylate, cycloserine,diarylquinoline, ethambutol, pyrazinamide, protionamide, rifampin, andthe like.

If desired, the respirable dry particles and respirable dry powders cancontain a suitable antiviral agent, such as oseltamivir, zanamavir,amantidine, rimantadine, ribavirin, gancyclovir, valgancyclovir,foscavir, Cytogam® (Cytomegalovirus Immune Globulin), pleconaril,rupintrivir, palivizumab, motavizumab, cytarabine, docosanol, denotivir,cidofovir, and acyclovir. The respirable dry particles and respirabledry powders can contain a suitable anti-influenza agent, such aszanamivir, oseltamivir, amantadine, or rimantadine.

Suitable antihistamines include clemastine, asalastine, loratadine,fexofenadine and the like.

Suitable cough suppressants include benzonatate, benproperine,clobutinal, diphenhydramine, dextromethorphan, dibunate, fedrilate,glaucine, oxalamine, piperidione, opiods such as codeine and the like.

Suitable brochodilators include short-acting beta₂ agonists, long-actingbeta₂ agonists (LABA), long-acting muscarinic anagonists (LAMA),combinations of LABAs and LAMAs, methylxanthines, short-actinganticholinergic agents (may also be referred to as short actinganti-muscarinic), long-acting bronchodilators, and the like.

Suitable short-acting beta₂ agonists include albuterol, epinephrine,pirbuterol, levalbuterol, metaproteronol, maxair, and the like.

Examples of albuterol sulfate formulations (also called salbutamol)include Inspiryl (AstraZeneca Plc), Salbutamol SANDOZ (Sanofi-Aventis),Asmasal clickhaler (Vectura Group Plc.), Ventolin® (GlaxoSmithKlinePlc), Salbutamol GLAND (GlaxoSmithKline Plc), Airomir® (TevaPharmaceutical Industries Ltd.), ProAir HFA (Teva PharmaceuticalIndustries Ltd.), Salamol (Teva Pharmaceutical Industries Ltd.), Ipramol(Teva Pharmaceutical Industries Ltd), Albuterol sulfate TEVA (TevaPharmaceutical Industries Ltd), and the like. Examples of epinephrineinclude Epinephine Mist KING (King Pharmaceuticals, Inc.), and the like.Examples of pirbuterol as pirbuterol acetate include Maxair® (TevaPharmaceutical Industries Ltd.), and the like. Examples of levalbuterolinclude Xopenex® (Sepracor), and the like. Examples of metaproteronolformulations as metaproteronol sulfate include Alupent® (BoehringerIngelheim GmbH), and the like.

Suitable LABAs include salmeterol, formoterol and isomers (e.g.,arformoterol), clenbuterol, tulobuterol, vilanterol (Revolair™),indacaterol, carmoterol, isoproterenol, procaterol, bambuterol,milveterol, olodaterol, and the like.

Examples of salmeterol formulations include salmeterol xinafoate asSerevent® (GlaxoSmithKline Plc), salmeterol as Inaspir (LaboratoriosAlmirall, S.A.), Advair® HFA (GlaxoSmithKline PLC), Advair Diskus®(GlaxoSmithKline PLC, Theravance Inc), Plusvent (Laboratorios Almirall,S.A.), VR315 (Novartis, Vectura Group PLC) and the like. Examples offormoterol and isomers (e.g., arformoterol) include Foster (ChiesiFarmaceutici S.p.A), Atimos (Chiesi Farmaceutici S.p.A, NycomedInternaional Management), Flutiform® (Abbott Laboratories, SkyePharmaPLC), MFF258 (Novartis AG), Formoterol clickhaler (Vectura Group PLC),Formoterol HFA (SkyePharma PLC), Oxis® (Astrazeneca PLC), Oxis pMDI(Astrazeneca), Foradil® Aerolizer (Novartis, Schering-Plough Corp,Merck), Foradil® Certihaler (Novartis, SkyePharma PLC), Symbicort®(AstraZeneca), VR632 (Novartis AG, Sandoz International GmbH), MFF258(Merck & Co Inc, Novartis AG), Alvesco® Combo (Nycomed InternationalManagement GmbH, Sanofi-Aventis, Sepracor Inc), Mometasone furoate(Schering-Plough Corp), and the like. Examples of clenbuterol includeVentipulmin® (Boehringer Ingelheim), and the like. Examples oftulobuterol include Hokunalin Tape (Abbott Japan Co., Ltd., Maruho Co.,Ltd.), and the like. Examples of vilanterol include Revolair™(GlaxoSmithKline PLC), GSK64244 (GlaxoSmithKline PLC), and the like.Examples of indacaterol include QAB149 (Novartis AG, SkyePharma PLC),QMF149 (Merck & Co Inc) and the like. Examples of carmoterol includeCHF4226 (Chiese Farmaceutici S.p.A., Mitsubishi Tanabe PharmaCorporation), CHF5188 (Chiesi Farmaceutici S.p.A), and the like.Examples of isoproterenol sulfate include Aludrin (Boehringer IngelheimGmbH) and the like. Examples of procaterol include Meptin clickhaler(Vectura Group PLC), and the like. Examples of bambuterol include Bambec(AstraZeneca PLC), and the like. Examples of milveterol includeGSK159797C (GlaxoSmithKline PLC), TD3327 (Theravance Inc), and the like.Examples of olodaterol include BI1744CL (Boehringer Ingelheim GmbH) andthe like.

Examples of LAMAs include tiotroprium (Spiriva), trospium chloride,glycopyrrolate, aclidinium, ipratropium and the like.

Examples of tiotroprium formulations include Spiriva(Boehringer-Ingleheim, Pfizer), and the like. Examples of glycopyrrolateinclude Robinul® (Wyeth-Ayerst), Robinul® Forte (Wyeth-Ayerst), NVA237(Novartis), and the like. Examples of aclidinium include Eklira® (ForestLabaoratories, Almirall), and the like.

Examples of combinations of LABAs and LAMAs include indacaterol withglycopyrrolate, formoterol with glycopyrrolate, indacaterol withtiotropium, olodaterol and tiotropium, vilanterol with a LAMA, and thelike. Examples of combinations of formoterol with glycopyrrolate includePT003 (Pearl Therapeutics) and the like. Examples of combinations ofolodaterol with tiotropium include BI1744 with Spirva (BoehringerIngelheim) and the like. Examples of combinations of vilanterol with aLAMA include GSK573719 with GSK642444 (GlaxoSmithKline PLC), and thelike.

Examples of combinations of indacaterol with glycopyrrolate includeQVA149A (Novartis), and the like.

Examples of methylxanthine include aminophylline, ephedrine,theophylline, oxtriphylline, and the like.

Examples of aminophylline formulations include Aminophylline BOEHRINGER(Boehringer Ingelheim GmbH) and the like. Examples of ephedrine includeBronkaid® (Bayer AG), Broncholate (Sanofi-Aventis), Primatene® (Wyeth),Tedral SA®, Marax (Pfizer Inc) and the like. Examples of theophyllineinclude Euphyllin (Nycomed International Management GmbH), Theo-dur(Pfizer Inc, Teva Pharmacetuical Industries Ltd) and the like. Examplesof oxtriphylline include Choledyl SA (Pfizer Inc) and the like.

Examples of short-acting anticholinergic agents include ipratropiumbromide, and oxitropium bromide.

Examples of ipratropium bromide formulations includeAtrovent®/Apovent/Inpratropio (Boehringer Ingelheim GmbH), Ipramol (TevaPharmaceutical Industries Ltd) and the like. Examples of oxitropiumbromide include Oxivent (Boehringer Ingelheim GmbH), and the like.

Suitable anti-inflammatory agents include leukotriene inhibitors,phosphodiesterase 4 (PDE4) inhibitors, other anti-inflammatory agents,and the like.

Suitable leukotriene inhibitors include montelukast formulations(cystinyl leukotriene inhibitors), masilukast, zafirleukast (leukotrieneD4 and E4 receptor inhibitors), pranlukast, zileuton (5-lipoxygenaseinhibitors), and the like.

Examples of montelukast (cystinyl leukotriene inhibitor) includeSingulair (Merck & Co Inc), Loratadine, montelukast sodium SCHERING(Schering-Plough Corp), MK0476C (Merck & Co Inc), and the like. Examplesof masilukast include MCC847 (AstraZeneca PLC), and the like. Examplesof zafirlukast (leukotriene D4 and E4 receptor inhibitor) includeAccolate® (AstraZeneca PLC), and the like. Examples of pranlukastinclude Azlaire (Schering-Plough Corp). Examples of zileuton (5-LO)include Zyflo® (Abbott Laboratories), Zyflo CR® (Abbott Laboratories,SkyePharma PLC), Zileuton ABBOTT LABS (Abbott Laboratories), and thelike. Suitable PDE4 inhibitors include cilomilast, roflumilast,oglemilast, tofimilast, and the like.

Examples of cilomilast formulations include Ariflo (GlaxoSmithKlinePLC), and the like. Examples of roflumilast include Daxas® (NycomedInternational Management GmbH, Pfizer Inc), APTA2217 (Mitsubishi TanabePharma Corporation), and the like. Examples of oglemilast includeGRC3886 (Forest Laboratories Inc), and the like. Examples of tofimilastinclude Tofimilast PFIZER INC (Pfizer Inc), and the like.

Other anti-inflammatory agents include omalizumab (anti-IgEimmunoglobulin Daiichi Sankyo Company, Limited), Zolair (anti-IgEimmunoglobulin, Genentech Inc, Novartis AG, Roche Holding Ltd), Solfa(LTD4 antagonist and phosphodiesterase inhibitor, Takeda PharmaceuticalCompany Limited), IL-13 and IL-13 receptor inhibitors (such as AMG-317,MILR1444A, CAT-354, QAX576, IMA-638, Anrukinzumab, IMA-026, MK-6105,DOM-0910, and the like), IL-4 and IL-4 receptor inhibitors (such asPitrakinra, AER-003, AIR-645, APG-201, DOM-0919, and the like), IL-1inhibitors such as canakinumab, CRTh2 receptor antagonists such asAZD1981 (CRTh2 receptor antagonist, AstraZeneca), neutrophil elastaseinhibitor such as AZD9668 (neutrophil elastase inhibitor, fromAstraZeneca), GW856553X Losmapimod (P38 kinase inhibitor,GlaxoSmithKline PLC), Arofylline LAB ALMIRALL (PDE-4 inhibitor,Laboratorios Almirall, S.A.), ABT761 (5-LO inhibitor, AbbottLaboratories), Zyflo® (5-LO inhibitor, Abbott Laboratories), BT061(anti-CD 4 mAb, Boehringer Ingelheim GmbH), Corns (inhaled lidocaine todecrease eosinophils, Gilead Sciences Inc), Prograf (IL-2-mediatedT-cell activation inhibitor, Astellas Pharma), Bimosiamose PFIZER INC(selectin inhibitor, Pfizer Inc), R411 (α4 β1/α4 β7 integrin antagonist,Roche Holdings Ltd), Tilade® (inflammatory mediator inhibitor,Sanofi-Aventis), Orenica® (T-cell co-stimulation inhibitor,Bristol-Myers Squibb Company), Soliris® (anti-05, AlexionPharmaceuticals Inc), Entorken® (Farmacija d.o.o.), Excellair® (Sykkinase siRNA, ZaBeCor Pharmaceuticals, Baxter International Inc), KB003(anti-GMCSF mAb, KaloBios Pharmaceuticals), Cromolyn sodiums (inhibitrelease of mast cell mediators): Cromolyn sodium BOEHRINGER (BoehringerIngelheim GmbH), Cromolyn sodium TEVA (Teva Pharmaceutical IndustriesLtd), Intal (Sanofi-Aventis), BI1744CL (oldaterol (β2-adrenoceptorantagonist) and tiotropium, Boehringer Ingelheim GmbH), NFκ-Binhibitors, CXR2 antagaonists, HLE inhibitors, HMG-CoA reductaseinhibitors and the like.

Anti-inflammatory agents also include compounds that inhibit/decreasecell signaling by inflammatory molecules like cytokines (e.g., IL-1,IL-4, IL-5, IL-6, IL-9, IL-13, IL-18 IL-25, IFN-α, IFN-β, and others),CC chemokines CCL-1-CCL28 (some of which are also known as, for example,MCP-1, CCL2, RANTES), CXC chemokines CXCL1-CXCL17 (some of which arealso know as, for example, IL-8, MIP-2), growth factors (e.g., GM-CSF,NGF, SCF, TGF-β, EGF, VEGF and others) and/or their respectivereceptors.

Some examples of the aforementioned anti-inflammatoryantagonists/inhibitors include ABN912 (MCP-1/CCL2, Novartis AG), AMG761(CCR4, Amgen Inc), Enbrel® (TNF, Amgen Inc, Wyeth), huMAb OX40LGENENTECH (TNF superfamily, Genentech Inc, AstraZeneca PLC), R4930 (TNFsuperfamily, Roche Holding Ltd), SB683699/Firategrast (VLA4,GlaxoSmithKline PLC), CNT0148 (TNFα, Centocor, Inc, Johnson & Johnson,Schering-Plough Corp); Canakinumab (IL-1β, Novartis); IsrapafantMITSUBISHI (PAF/IL-5, Mitsubishi Tanabe Pharma Corporation); IL-4 andIL-4 receptor antagonists/inhibitors: AMG317 (Amgen Inc), BAY169996(Bayer AG), AER-003 (Aerovance), APG-201 (Apogenix); IL-5 and IL-5receptor antagonists/inhibitors: MEDI563 (AstraZeneca PLC, Medlmmune,Inc), Bosatria® (GlaxoSmithKline PLC), Cinquil® (Ception Therapeutic),TMC120B (Mitsubishi Tanabe Pharma Corporation), Bosatria(GlaxoSmithKline PLC), Reslizumab SCHERING (Schering-Plough Corp);MEDI528 (IL-9, AstraZeneca, Medlmmune, Inc); IL-13 and IL-13 receptorantagonists/inhibitors: TNX650 GENENTECH (Genentech), CAT-354(AstraZeneca PLC, Medlmmune), AMG-317 (Takeda Pharmaceutical CompanyLimited), MK6105 (Merck & Co Inc), IMA-026 (Wyeth), IMA-638 Anrukinzumab(Wyeth), MILR1444A/Lebrikizumab (Genentech), QAX576 (Novartis), CNTO-607(Centocor), MK-6105 (Merck, CSL); Dual IL-4 and IL-13 inhibitors:AIR645/ISIS369645 (ISIS Altair), DOM-0910 (GlaxoSmithKline, Domantis),Pitrakinra/AER001/Aerovant™ (Aerovance Inc), AMG-317 (Amgen), and thelike.

Suitable steroids include corticosteroids, combinations ofcorticosteroids and LABAs, combinations of corticosteroids and LAMAs,combinations of corticosteroids, LABAs and LAMAs, and the like.

Suitable corticosteroids include budesonide, fluticasone, flunisolide,triamcinolone, beclomethasone, mometasone, ciclesonide, dexamethasone,and the like.

Examples of budesonide formulations include Captisol-Enabled BudesonideSolution for Nebulization (AstraZeneca PLC), Pulmicort® (AstraZenecaPLC), Pulmicort® Flexhaler (AstraZeneca Plc), Pulmicort® HFA-MDI(AstraZeneca PLC), Pulmicort Respules® (AstraZeneca PLC), Inflammide(Boehringer Ingelheim GmbH), Pulmicort® HFA-MDI (SkyePharma PLC), UnitDose Budesonide ASTRAZENECA (AstraZeneca PLC), Budesonide Modulite(Chiesi Farmaceutici S.p.A), CHF5188 (Chiesi Farmaceutici S.p.A),Budesonide ABBOTT LABS (Abbott Laboratories), Budesonide clickhaler(Vestura Group PLC), Miflonide (Novartis AG), Xavin (Teva PharmaceuticalIndustries Ltd.), Budesonide TEVA (Teva Pharmaceutical Industries Ltd.),Symbicort® (AstraZeneca K.K., AstraZeneca PLC), VR632 (Novartis AG,Sandoz International GmbH), and the like.

Examples of fluticasone propionate formulations include FlixotideEvohaler (GlaxoSmithKline PLC), Flixotide Nebules (GlaxoSmithKline Plc),Flovent® (GlaxoSmithKline Plc), Flovent® Diskus (GlaxoSmithKline PLC),Flovent® HFA (GlaxoSmithKline PLC), Flovent® Rotadisk (GlaxoSmithKlinePLC), Advair® HFA (GlaxoSmithKline PLC, Theravance Inc), Advair Diskus®(GlaxoSmithKline PLC, Theravance Inc.), VR315 (Novartis AG, VecturaGroup PLC, Sandoz International GmbH), and the like. Other formulationsof fluticasone include fluticasone as Flusonal (Laboratorios Almirall,S.A.), fluticasone furoate as GW685698 (GlaxoSmithKline PLC, ThervanceInc.), Plusvent (Laboratorios Almirall, S.A.), Flutiform® (AbbottLaboratories, SkyePharma PLC), and the like.

Examples of flunisolide formulations include Aerobid (ForestLaboratories Inc), Aerospan® (Forest Laboratories Inc), and the like.Examples of triamcinolone include Triamcinolone ABBOTT LABS (AbbottLaboratories), Azmacort® (Abbott Laboratories, Sanofi-Aventis), and thelike. Examples of beclomethasone dipropionate include Beclovent(GlaxoSmithKline PLC), QVAR® (Johnson & Johnson, Schering-Plough Corp,Teva Pharmacetucial Industries Ltd), Asmabec clickhaler (Vectura GroupPLC), Beclomethasone TEVA (Teva Pharmaceutical Industries Ltd), Vanceril(Schering-Plough Corp), BDP Modulite (Chiesi Farmaceutici S.p.A.),Clenil (Chiesi Farmaceutici S.p.A), Beclomethasone dipropionate TEVA(Teva Pharmaceutical Industries Ltd), and the like. Examples ofmometasone include QAB149 Mometasone furoate (Schering-Plough Corp),QMF149 (Novartis AG), Fomoterol fumarate, mometoasone furoate(Schering-Plough Corp), MFF258 (Novartis AG, Merck & Co Inc), Asmanex®Twisthaler (Schering-Plough Corp), and the like. Examples of cirlesonideinclude Alvesco® (Nycomed International Management GmbH, Sepracor,Sanofi-Aventis, Tejin Pharma Limited), Alvesco® Combo (NycomedInternational Management GmbH, Sanofi-Aventis), Alvesco® HFA (NycomedIntenational Management GmbH, Sepracor Inc), and the like. Examples ofdexamethasone include DexPak® (Merck), Decadron® (Merck), Adrenocot,CPC-Cort-D, Decaject-10, Solurex and the like. Other corticosteroidsinclude Etiprednol dicloacetate TEVA (Teva Pharmaceutical IndustriesLtd), and the like.

Combinations of corticosteroids and LABAs include salmeterol withfluticasone, formoterol with budesonide, formoterol with fluticasone,formoterol with mometasone, indacaterol with mometasone, and the like.

Examples of salmeterol with fluticasone include Plusvent (LaboratoriosAlmirall, S.A.), Advair® HFA (GlaxoSmithKline PLC), Advair® Diskus(GlaxoSmithKline PLV, Theravance Inc), VR315 (Novartis AG, Vectura GroupPLC, Sandoz International GmbH) and the like. Examples of formoterolwith budesonide include Symbicort® (AstraZeneca PLC), VR632 (NovartisAG, Vectura Group PLC), and the like. Examples of vilanterol withfluticasone include GSK642444 with fluticasone and the like. Examples offormoterol with fluticasone include Flutiform® (Abbott Laboratories,SkyePharma PLC), and the like. Examples of formoterol with mometasoneinclude Dulera®/MFF258 (Novartis AG, Merck & Co Inc), and the like.Examples of indacaterol with mometasone include QAB 149 Mometasonefuroate (Schering-Plough Corp), QMF149 (Novartis AG), and the like.Combinations of corticosteroids with LAMAs include fluticasone withtiotropium, budesonide with tiotropium, mometasone with tiotropium,salmeterol with tiotropium, formoterol with tiotropium, indacaterol withtiotropium, vilanterol with tiotropium, and the like. Combinations ofcorticosteroids with LAMAs and LABAs include, for example, fluticasonewith salmeterol and tiotropium.

Other anti-asthma molecules include: ARD111421 (VIP agonist, AstraZenecaPLC), AVE0547 (anti-inflammatory, Sanofi-Aventis), AVE0675 (TLR agonist,Pfizer, Sanofi-Aventis), AVE0950 (Syk inhibitor, Sanofi-Aventis),AVE5883 (NK1/NK2 antagonist, Sanofi-Aventis), AVE8923 (tryptase betainhibitor, Sanofi-Aventis), CGS21680 (adenosine A2A receptor agonist,Novartis AG), ATL844 (A2B receptor antagonist, Novartis AG), BAY443428(tryptase inhibitor, Bayer AG), CHF5407 (M3 receptor inhibitor, ChiesiFarmaceutici S.p.A.), CPLA2 Inhibitor WYETH (CPLA2 inhibitor, Wyeth),IMA-638 (IL-13 antagonist, Wyeth), LAS100977 (LABA, LaboratoriosAlmirall, S.A.), MABA (M3 and β2 receptor antagonist, ChiesiFarmaceutici S.p.A), R1671 (mAb, Roche Holding Ltd), CS003 (Neurokininreceptor antagonist, Daiichi Sankyo Company, Limited), DPC168 (CCRantagonist, Bristol-Myers Squibb), E26 (anti-IgE, Genentech Inc), HAE1(Genentech), IgE inhibitor AMGEN (Amgen Inc), AMG853 (CRTH2 and D2receptor antagonist, Amgen), IPL576092 (LSAID, Sanofi-Aventis), EPI2010(antisense adenosine 1, Chiesi Farmaceutici S.p.A.), CHF5480 (PDE-4inhibitor, Chiesi Farmaceutici S.p.A.), KI04204 (corticosteroid, AbbottLaboratories), SVT47060 (Laboratorios Salvat, S.A.), VML530 (leukotrienesynthesis inhibitor, Abbott Laboratories), LAS35201 (M3 receptorantagonist, Laboratorios Almirall, S.A.), MCC847 (D4 receptorantagonist, Mitsubishi Tanabe Pharma Corporation), MEM1414 (PDE-4inhibitor, Roche), TA270 (5-LO inhibitor, Chugai Pharmaceutical Co Ltd),TAK661 (eosinophil chemotaxis inhibitor, Takeda Pharmaceutical CompanyLimited), TBC4746 (VLA-4 antagonist, Schering-Plough Corp), VR694(Vectura Group PLC), PLD177 (steroid, Vectura Group PLC), KI03219(corticosteroid+LABA, Abbott Laboratories), AMG009 (Amgen Inc), AMG853(D2 receptor antagonist, Amgen Inc);

AstraZeneca PLC: AZD1744 (CCR3/histamine-1 receptor antagonist, AZD1419(TLR9 agonist), Mast Cell inhibitor ASTRAZENECA, AZD3778 (CCRantagonist), DSP3025 (TLR7 agonist), AZD1981 (CRTh2 receptorantagonist), AZD5985 (CRTh2 antagonist), AZD8075 (CRTh2 antagonist),AZD1678, AZD2098, AZD2392, AZD3825 AZD8848, AZD9215, ZD2138 (5-LOinhibitor), AZD3199 (LABA);

GlaxoSmithKline PLC: GW328267 (adenosine A2 receptor agonist), GW559090(α4 integrin antagonist), GSK679586 (mAb), GSK597901 (adrenergic (32agonist), AM103 (5-LO inhibitor), GSK256006 (PDE4 inhibitor), GW842470(PDE-4 inhibitor), GSK870086 (glucocorticoid agonist), GSK159802 (LABA),GSK256066 (PDE-4 inhibitor), GSK642444 (LABA, adrenergic β2 agonist),GSK64244 and Revolair (fluticasone/vilanterol), GSK799943(corticosteroid), GSK573719 (mAchR antagonist), and GSK573719;

Pfizer Inc: PF3526299, PF3893787, PF4191834 (FLAP antagonist), PF610355(adrenergic β2 agonist), CP664511 (α4β1/VCAM-1 interaction inhibitor),CP609643 (inhibitor of α4β1/VCAM-1 interactions), CP690550 (JAK3inhibitor), SAR21609 (TLR9 agonist), AVE7279 (Th1 switching), TBC4746(VLA-4 antagonist); R343 (IgE receptor signaling inhibitor), SEP42960(adenosine A3 antagonist);

Sanofi-Aventis: MLN6095 (CrTH2 inhibitor), SAR137272 (A3 antagonist),SAR21609 (TLR9 agonist), SAR389644 (DP1 receptor antagonist), SAR398171(CRTH2 antagonist), SSR161421 (adenosine A3 receptor antagonist);

Merck & Co Inc: MK0633, MK0633, MK0591 (5-LO inhibitor), MK886(leukotriene inhibitor), BIO1211 (VLA-4 antagonist); Novartis AG: QAE397(long-acting corticosteroid), QAK423, QAN747, QAP642 (CCR3 antagonist),QAX935 (TLR9 agonist), NVA237 (LAMA).

The pharmaceutically active agent can also be selected from the groupconsisting of transient receptor potential (TRP) channel agonists. Incertain embodiments, the TRP agonist is a TRPC, TRPV, TRPM and/or TRPA1subfamily agonist. In some embodiments, the TRP channel agonist isselected from the group consisting of TRPV2, TRPV3, TRPV4, TRPC6, TRPM6,and/or TRPA1 agonist. Suitable TRP channel agonists may be selected fromthe group consisting of allyl isothiocyanate (AITC), benyzlisothiocyanate (BITC), phenyl isothiocyanate, isopropyl isothiocyanate,methyl isothiocyanate, diallyl disulfide, acrolein (2-propenal),disulfuram (Antabuse®), farnesyl thiosalicylic acid (FTS), farnesylthioacetic acid (FTA), chlodantoin (Sporostacin®, topical fungicidal),(15-d-PGJ2), 5,8,11,14 eicosatetraynoic acid (ETYA), dibenzoazepine,mefenamic acid, fluribiprofen, keoprofen, diclofenac, indomethacin, SCalkyne (SCA), pentenal, mustard oil alkyne (MOA), iodoacetamine,iodoacetamide alkyne, (2-aminoethyl) methanethiosulphonate (MTSEA),4-hydroxy-2-noneal (HNE), 4-hydroxy xexenal (HHE),2-chlorobenzalmalononitrile, N-chloro tosylamide (chloramine-T),formaldehyde, isoflurane, isovelleral, hydrogen peroxide, URB597,thiosulfinate, Allicin (a specific thiosulfinate), flufenamic acid,niflumic acid, carvacrol, eugenol, menthol, gingerol, icilin, methylsalicylate, arachidonic acid, cinnemaldehyde, super sinnemaldehyde,tetrahydrocannabinol (THC or Δ⁹-THC), cannabidiol (CBD), cannabichromene(CBC), cannabigerol (CBG), THC acid (THC-A), CBD acid (CBD-A), Compound1 (AMG5445),4-methyl-N-[2,2,2-trichloro-1-(4-chlorophenylsulfanyl)ethyl]benzamide,N-[2,2,2-trichloro-1-(4-chlorophenylsulfanyl)ethyl]acetamid, AMG9090,AMG5445, 1-oleoyl-2-acetyl-sn-glycerol (OAG), carbachol, diacylglycerol(DAG), 1,2-Didecanoylglycerol, flufenamate/flufenamic acid,niflumate/niflumic acid, hyperforin, 2-aminoethoxydiphenyl borate(2-APB), diphenylborinic anhydride (DPBA), delta-9-tetrahydrocannabinol(Δ⁹-THC or THC), cannabiniol (CBN), 2-APB, O-1821,11-hydroxy-Δ9-tetrahydrocannabinol, nabilone, CP55940, HU-210,HU-211/dexanabinol, HU-331, HU-308, JWH-015,WIN55,212-2,2-Arachidonoylglycerol (2-AG), Arvil, PEA, AM404, O-1918,JWH-133, incensole, incensole acetate, menthol, eugenol, dihydrocarveol,carveol, thymol, vanillin, ethyl vanillin, cinnemaldehyde, 2aminoethoxydiphenyl borate (2-APB), diphenylamine (DPA), diphenylborinicanhydride (DPBA), camphor, (+)-borneol, (−)-isopinocampheol,(−)-fenchone, (−)-trans-pinocarveol, isoborneol, (+)-camphorquinone,(−)-α-thujone, α-pinene oxide, 1,8-cineole/eucalyptol, 6-butyl-m-cresol,carvacrol, p-sylenol, kreosol, propofol, p-cymene, (−)-isoppulegol,(−)-carvone, (+)-dihydrocarvone, (−)-menthone, (+)-linalool, geraniol,1-isopropyl-4-methylbicyclo[3.1.0]hexan-4-ol, 4αPDD, GSK1016790A,5′6′Epoxyeicosatrienoic (5′6′-EET), 8′9′Epoxyeicosatrienoic (8′9′-EET),APP44-1, RN1747, Formulation Ib WO200602909, Formulation IIbWO200602909, Formulation IIc WO200602929, Formulation IId WO200602929,Formulation IIIb WO200602929, Formulation Inc WO200602929, arachidonicacid (AA), 12-O-Tetradecanoylphorbol-13-acetate (TPA)/phorbol12-myristate 13-acetate (PMA), bisandrographalide (BAA), incensole,incensole acetate, Compound IX WO2010015965, Compound X WO2010015965,Compound XI WO2010015965, Compound XII WO2010015965, WO2009004071,WO2006038070, WO2008065666, Formula VII WO2010015965, Formula IVWO2010015965, dibenzoazepine, dibenzooxazepine, Formula I WO2009071631,N-{(1S)-1-[({(4R)-1-[(4-chlorophenyl)sulfonyl]-3-oxohexahydro-1Hazepin-4-yl}amino)carbonyl]-3-methylbutyl}-1-benzothiophen-2-carboxamide,N-{(1S)-1-R{(4R)-1-[(4-fluorophenyl)sulfonyl]-3-oxohexahydro-1H-azepin-4-yl}amino)carbonyl]-3-methylbutyl}-1-benzothiophen-2-carboxamide,N-{(1S)-1-[({(4R)-1-[(2-cyanophenyl)sulfonyl]-3-oxohexahydro-1H-azepin-4-yl}amino)carbonyl]-3-methylbutyl}-1-methyl-1H-indole-2-carboxamide, andN-{(1S)-1-[({(4R)-1-[(2-cyanophenyl)sulfonyl]hexahydro-1H-azepin-4-yl}amino)carbonyl]-3-methylbutyl}-1-methyl-1H-indole-2-carboxamide.

Suitable expectorants include guaifenesin, guaiacolculfonate, ammoniumchloride, potassium iodide, tyloxapol, antimony pentasulfide and thelike.

Suitable vaccines include nasally inhaled influenza vaccines and thelike.

Suitable macromolecules include proteins and large peptides,polysaccharides and oligosaccharides, DNA and RNA nucleic acid moleculesand their analogs having therapeutic, prophylactic or diagnosticactivities. Proteins can include growth factors, hormones, cytokines(e.g., chemokines), and antibodies. As used herein, antibodies caninclude: all types of immunoglobulins, e.g. IgG, IgM, IgA, IgE, IgD,etc., from any source, e.g. human, rodent, rabbit, cow, sheep, pig, dog,other mammals, chicken, other avian, aquatic animal species etc.,monoclonal and polyclonal antibodies, single chain antibodies (includingIgNAR (single-chain antibodies derived from sharks)), chimericantibodies, bifunctional/bispecific antibodies, humanized antibodies,human antibodies, and complementary determining region (CDR)-graftedantibodies, that are specific for the target protein or fragmentsthereof, and also include antibody fragments, including Fab, Fab′,F(ab′)2, scFv, Fv, camelbodies, microantibodies, nanobodies, andsmall-modular immunopharmaceuticals (SMIPs). Nucleic acid moleculesinclude DNA, e.g. encoding genes or gene fragments, or RNA, includingmRNA, antisense molecules, such as antisense RNA, RNA molecules involvedin RNA interference (RNAi), such as microRNA (miRNA), small interferingRNA (siRNA) and small hairpin RNA (shRNA), ribozymes or other moleculescapable of inhibiting transcription and/or translation. Preferredmacromolecules have a molecular weight of at least 800 Da, at least 3000Da or at least 5000 Da.

In preferred embodiments, the respirable dry powder or respirable dryparticle comprises a therapeutic antibody. In certain preferredembodiments, the antibody is a monoclonal antibody. In certain preferredembodiments, the antibody is a single chain antibody, a chimericantibody, a bifunctional/bispecific antibody, a humanized antibody, or acombination thereof. In preferred embodiments, the antibody is selectedfrom the group consisting of: monoclonal antibodies, e.g. Abciximab(ReoPro®, chimeric), Adalimumab (Humira®, human), Alemtuzumab (Campath®,humanized), Basiliximab (Simulect®, chimeric), Belimumab (Benlysta®,human), Bevacizumab (Avastin®, humanized), Brentuximab vedotin(Adcetris®, chimeric), Canakinumab (Ilaris®, human), Cetuximab(Erbitux®, chimeric), Certolizumab pegol (Cimzia®, humanized),Daclizumab (Zenapax®, humanized), Denosumab (Prolia®, Xgeva®, human),Eculizumab (Soliris®, humanized), Efalizumab (Raptiva®, humanized),Gemtuzumab (Mylotarg®, humanized), Golimumab (Simponi®, human),Ibritumomab tiuxetan (Zevalin®, murin), Infliximab (Remicade®,chimeric), Ipilimumab (MDX-101) (Yervoy®, human), Muromonab-CD3(Orthoclone OKT3, murine), Natalizumab (Tysabri®, humanized), Ofatumumab(Arzerra®, human), Omalizumab (Xolair®, humanized), Palivizumab(Synagis®, humanized), Panitumumab (Vectibix®, human), Ranibizumab(Lucentis®, humanized), Rituximab (Rituxan®, Mabthera®, chimeric),Tocilizumab (or Atlizumab) (Actemra® and RoActemra®, humanized),Tositumomab (Bexxar®, murine), Trastuzumab (Herceptin®, humanized), andbispecific antibodies, e.g. catumaxomab (Removab®, rat-mouse hybridmonoclonal antibody).

Selected macromolecule active agents for systemic applications include,but are not limited to: Ventavis® (Iloprost), Calcitonin, Erythropoietin(EPO), Factor IX, Granulocyte Colony Stimulating Factor (G-CSF),Granulocyte Macrophage Colony, Stimulating Factor (GM-CSF), GrowthHormone, Insulin, TGF-beta, Interferon Alpha, Interferon Beta,Interferon Gamma, Luteinizing Hormone Releasing Hormone (LHRH), folliclestimulating hormone (FSH), Ciliary Neurotrophic Factor, Growth HormoneReleasing Factor (GRF), Insulin-Like Growth Factor, Insulinotropin,Interleukin-1 Receptor Antagonist, Interleukin-3, Interleukin-4,Interleukin-6, Macrophage Colony Stimulating Factor (M-CSF), ThymosinAlpha 1, IIb/IIIa Inhibitor, Alpha-1 Antitrypsin, Anti-RSV Antibody,palivizumab, motavizumab, and ALN-RSV, Cystic Fibrosis TransmembraneRegulator (CFTR) Gene, Deoxyribonuclase (DNase), Heparin,Bactericidal/Permeability Increasing Protein (BPI), Anti-Cytomegalovirus(CMV) Antibody, Interleukin-1 Receptor Antagonist, and the like,alpha-defensins (e.g. human neutrophil proteins (HNPs): HNP1, 2, 3, and4; human defensins 5 and 6 (HD5 and HD6)), beta-defensins (HBD1, 2, 3,and 4), or Θ-defensins/retrocyclins, GLP-1 analogs (liraglutide,exenatide, etc.), Domain antibodies (dAbs), Pramlintide acetate(Symlin), Leptin analogs, Synagis (palivizumab, MedImmune) andcisplatin. In certain preferred embodiments, the respirable dry powderor respirable dry particle comprises a macromolecule involved in intra-or inter-cellular signaling, such as a growth factor, a cytokine, achemokine or a hormone. In preferred embodiments, the respirable drypowder or respirable dry particle comprises a hormone. In certainpreferred embodiments, the hormone is insulin.

Selected therapeutics helpful for chronic maintenance of CF includeantibiotics/macrolide antibiotics, bronchodilators, inhaled LABAs, andagents to promote airway secretion clearance. Suitable examples ofantibiotics/macrolide antibiotics include tobramycin, azithromycin,ciprofloxacin, colistin, aztreonam and the like. Another exemplaryantibiotic/macrolide is levofloxacin. Suitable examples ofbronchodilators include inhaled short-acting bet_(a2) agonists such asalbuterol, and the like. Suitable examples of inhaled LABAs includesalmeterol, formoterol, and the like. Suitable examples of agents topromote airway secretion clearance include Pulmozyme (dornase alfa,Genentech) hypertonic saline, DNase, heparin, and the like. Selectedtherapeutics helpful for the prevention and/or treatment of CF includeVX-770 (Vertex Pharmaceuticals) and amiloride.

Selected therapeutics helpful for the treatment of idiopathic pulmonaryfibrosis include Metelimumab (CAT-192) (TGF-β1 mAb inhibitor, Genzyme),Aerovant™ (AER001, pitrakinra) (Dual IL-13, IL-4 protein antagonist,Aerovance), Aeroderm™ (PEGylated Aerovant, Aerovance), microRNA, RNAi,and the like.

In preferred embodiments, the respirable dry powder or respirable dryparticle comprises an antibiotic, such as a macrolide (e.g.,azithromycin, clarithromycin and erythromycin), a tetracycline (e.g.,doxycycline, tigecycline), a fluoroquinolone (e.g., gemifloxacin,levofloxacin, ciprofloxacin and mocifloxacin), a cephalosporin (e.g.,ceftriaxone, defotaxime, ceftazidime, cefepime), a penicillin (e.g.,amoxicillin, amoxicillin with clavulanate, ampicillin, piperacillin, andticarcillin) optionally with a β-lactamase inhibitor (e.g., sulbactam,tazobactam and clavulanic acid), such as ampicillin-sulbactam,piperacillin-tazobactam and ticarcillin with clavulanate, anaminoglycoside (e.g., amikacin, arbekacin, gentamicin, kanamycin,neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin,tobramycin, and apramycin), a penem or carbapenem (e.g. doripenem,ertapenem, imipenem and meropenem), a monobactam (e.g., aztreonam), anoxazolidinone (e.g., linezolid), vancomycin, glycopeptide antibiotics(e.g. telavancin), tuberculosis-mycobacterium antibiotics, tobramycin,azithromycin, ciprofloxacin, colistin, and the like. In a preferredembodiment, the respirable dry powder or respirable dry particlecomprises levofloxacin. In another preferred embodiment, the respirabledry powder or respirable dry particle comprises aztreonam or apharmaceutically acceptable salt thereof (i.e., Cayston®). In a furtherpreferred embodiment, the respirable dry powder or respirable dryparticle does not comprise tobramycin. In another embodiment, therespirable dry powder or respirable dry particle does not compriselevofloxacin. In another embodiment, the respirable dry powder orrespirable dry particle does not comprise Cayston®.

In preferred embodiments, the respirable dry powder or respirable dryparticle comprises a LABA, such as salmeterol, formoterol and isomers(e.g., arformoterol), clenbuterol, tulobuterol, vilanterol (Revolair™),indacaterol, carmoterol, isoproterenol, procaterol, bambuterol,milveterol, and the like. In a further preferred embodiment, therespirable dry powder or respirable dry particle comprises formoterol.In a further preferred embodiment, the respirable dry powder orrespirable dry particle comprises salmeterol. When the dry powders areintended for treatment of CF, preferred additional therapeutic agentsare short-acting beta agonists (e.g., albuterol), antibiotics (e.g.,levofloxacin), recombinant human deoxyribonuclease I (e.g., dornasealfa, also known as DNAse), sodium channel blockers (e.g., amiloride),and combinations thereof.

In preferred embodiments, the respirable dry powder or respirable dryparticle comprises a LAMA, such as tiotroprium, glycopyrrolate,aclidinium, ipratropium and the like. In a further preferred embodiment,the respirable dry powder or respirable dry particle comprisestiotropium.

In preferred embodiments, the respirable dry powder or respirable dryparticle comprises a corticosteroid, such as budesonide, fluticasone,flunisolide, triamcinolone, beclomethasone, mometasone, ciclesonide,dexamethasone, and the like. In a further preferred embodiment, therespirable dry powder or respirable dry particle comprises fluticasone.

In preferred embodiments, the respirable dry powder or respirable dryparticle comprises a combination of two or more of the following; aLABA, a LAMA, and a corticosteroid. In a further preferred embodiment,the respirable dry powder or respirable dry particle comprisesfluticasone and salmeterol. In a further preferred embodiment, therespirable dry powder or respirable dry particle comprises fluticasone,salmeterol, and tiotropium.

When an additional therapeutic agent is administered to a patient with adry powder or dry particles disclosed herein, the agent and the drypowder or dry particles are administered to provide overlap of thetherapeutic effect of the additional therapeutic agent with theadministration of the dry powder or dry particles. For example, a LABAsuch as formoterol, or a short-acting beta agonist such as albuterol canbe administered to the patient before a dry powder or dry particle, asdescribed herein, is administered.

In preferred embodiments, the respirable dry powder or respirable dryparticle does not comprise a surfactant, such asL-alpha-phosphatidylcholine dipalmitoyl (“DPPC”), diphosphatidylglycerol (DPPG), 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS),1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DSPC),1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE),1-palmitoyl-2-oleoylphosphatidylcholine (POPC), fatty alcohols,polyoxyethylene-9-lauryl ether, surface active fatty, acids, sorbitantrioleate (Span 85), glycocholate, surfactin, poloxomers, sorbitan fattyacid esters, tyloxapol, phospholipids, or alkylated sugars.

Dry Powder and Dry Particle Properties

The dry particles of the invention are preferably small and dispersible,and can be sodium cation (Na⁺) and/or potassium cation (K⁺) dense.Generally, the dry particles of the invention have a VMGD as measured byHELOS/RODOS at 1.0 bar of about 10 μm or less (e.g., about 0.1 μm toabout 10 μm). Preferably, the dry particles of the invention have a VMGDof about 9 μm or less (e.g., about 0.1 μm to about 9 μm), about 8 μm orless (e.g., about 0.1 μm to about 8 μm), about 7 μm or less (e.g., about0.1 μm to about 7 μm), about 6 μm or less (e.g., about 0.1 μm to about 6μm), about 5 μm or less (e.g., less than 5 μm, about 0.1 μm to about 5μm), about 4 μm or less (e.g., 0.1 μm to about 4 μm), about 3 μm or less(e.g., 0.1 μm to about 3 μm), about 2 μm or less (e.g., 0.1 μm to about2 μm), about 1 μm or less (e.g., 0.1 μm to about 1 μm), about 1 μm toabout 6 μm, about 1 μm to about 5 μm, about 1 μm to about 4 μm, about 1μm to about 3 μm, or about 1 μm to about 2 μm as measured by HELOS/RODOSat 1.0 bar.

The respirable dry powders of the invention can have poor flowproperties, such as bulk flow properties, for example as assessed byHausner Ratio, as described herein. Yet, surprisingly, the powders arehighly dispersible. This is surprising because flow properties anddispersibility are both known to be negatively affected by particleagglomeration or aggregation. Thus, it was unexpected that particlesthat have poor flow characteristics, such as bulk flow characteristics,would be highly dispersible.

The respirable dry powders can have a Hausner Ratio that is at least1.5, and can be at least 1.6, at least 1.7, at least 1.8, at least 1.9,at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, atleast 2.5, at least 2.6 or at least 2.7.

Generally, the dry particles of the invention are dispersible, and have1 bar/4 bar and/or 0.5 bar/4 bar and/or 0.2 bar/4 bar and/or 0.2 bar/2bar of about 2.2 or less (e.g., about 1.0 to about 2.2) or about 2.0 orless (e.g., about 1.0 to about 2.0). Preferably, the dry particles ofthe invention have 1 bar/4 bar and/or 0.5 bar/4 bar of about 1.9 or less(e.g., about 1.0 to about 1.9), about 1.8 or less (e.g., about 1.0 toabout 1.8), about 1.7 or less (e.g., about 1.0 to about 1.7), about 1.6or less (e.g., about 1.0 to about 1.6), about 1.5 or less (e.g., about1.0 to about 1.5), about 1.4 or less (e.g., about 1.0 to about 1.4),about 1.3 or less (e.g., less than 1.3, about 1.0 to about 1.3), about1.2 or less (e.g., 1.0 to about 1.2), about 1.1 or less (e.g., 1.0 toabout 1.1 μm) or the dry particles of the invention have 1 bar/4 barand/or 0.5 bar/4 bar of about 1.0. Preferably 1 bar/4 bar and/or 0.5bar/4 bar are measured by laser diffraction using a HELOS/RODOS system.

Alternatively or in addition, the respirable dry particles of theinvention can have an MMAD of about 10 microns or less, such as an MMADof about 0.5 micron to about 10 microns. Preferably, the dry particlesof the invention have an MMAD of about 5 microns or less (e.g., about0.5 micron to about 5 microns, preferably about 1 micron to about 5microns), about 4 microns or less (e.g., about 1 micron to about 4microns), about 3.8 microns or less (e.g., about 1 micron to about 3.8microns), about 3.5 microns or less (e.g., about 1 micron to about 3.5microns), about 3.2 microns or less (e.g., about 1 micron to about 3.2microns), about 3 microns or less (e.g., about 1 micron to about 3.0microns), about 2.8 microns or less (e.g., about 1 micron to about 2.8microns), about 2.2 microns or less (e.g., about 1 micron to about 2.2microns), about 2.0 microns or less (e.g., about 1 micron to about 2.0microns) or about 1.8 microns or less (e.g., about 1 micron to about 1.8microns).

Alternatively or in addition, the respirable dry powders and dryparticles of the invention can have an FPF of less than about 5.6microns (FPF<5.6 μm) of at least about 20%, at least about 30%, at leastabout 40%, preferably at least about 45%, at least about 50%, at leastabout 55%, at least about 60%, at least about 65%, or at least about70%.

Alternatively or in addition, the dry powders and dry particles of theinvention have a FPF of less than 5.0 microns (FPF_TD<5.0 μm) of atleast about 20%, at least about 30%, at least about 45%, preferably atleast about 40%, at least about 45%, at least about 50%, at least about60%, at least about 65% or at least about 70%. Alternatively or inaddition, the dry powders and dry particles of the invention have a FPFof less than 5.0 microns of the emitted dose (FPF ED<5.0 μm) of at leastabout 45%, preferably at least about 50%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,or at least about 85%. Alternatively or in addition, the dry powders anddry particles of the invention can have an FPF of less than about 3.4microns (FPF<3.4 μm) of at least about 20%, preferably at least about25%, at least about 30%, at least about 35%, at least about 40%, atleast about 45%, at least about 50%, or at least about 55%.

Alternatively or in addition, the respirable dry powders and dryparticles of the invention have a tap density of about 0.1 g/cm³ toabout 1.0 g/cm³. For example, the small and dispersible dry particleshave a tap density of about 0.1 g/cm³ to about 0.9 g/cm³, about 0.2g/cm³ to about 0.9 g/cm³, about 0.2 g/cm³ to about 0.9 g/cm³, about 0.3g/cm³ to about 0.9 g/cm³, about 0.4 g/cm³ to about 0.9 g/cm³, about 0.5g/cm³ to about 0.9 g/cm³, or about 0.5 g/cm³ to about 0.8 g/cm³, greaterthan about 0.4 g/cc, greater than about 0.5 g/cc, greater than about 0.6g/cc, greater than about 0.7 g/cc, about 0.1 g/cm³ to about 0.8 g/cm³,about 0.1 g/cm³ to about 0.7 g/cm³, about 0.1 g/cm³ to about 0.6 g/cm³,about 0.1 g/cm³ to about 0.5 g/cm³, about 0.1 g/cm³ to about 0.4 g/cm³,about 0.1 g/cm³ to about 0.3 g/cm³, less than 0.3 g/cm³. In a preferredembodiment, tap density is greater than about 0.4 g/cm³. In anotherpreferred embodiment, tap density is greater than about 0.5 g/cm³.Alternatively, tap density is less than about 0.4 g/cc.

Alternatively or in addition, the respirable dry powders and dryparticles of the invention can have a water or solvent content of lessthan about 15% by weight of the respirable dry particle. For example,the respirable dry particles of the invention can have a water orsolvent content of less than about 15% by weight, less than about 13% byweight, less than about 11.5% by weight, less than about 10% by weight,less than about 9% by weight, less than about 8% by weight, less thanabout 7% by weight, less than about 6% by weight, less than about 5% byweight, less than about 4% by weight, less than about 3% by weight, lessthan about 2% by weight, less than about 1% by weight or be anhydrous.The respirable dry particles of the invention can have a water orsolvent content of less than about 6% and greater than about 1%, lessthan about 5.5% and greater than about 1.5%, less than about 5% andgreater than about 2%, about 2%, about 2.5%, about 3%, about 3.5%, about4%, about 4.5% about 5%.

The dissolution of the respirable dry powders and respirable dryparticles upon deposition of the dry powder or particles in the lungsmay be rapid or sustained. The period of sustained dissolution, in oneaspect, is on the time scale of minutes, for example half of the calciumcation of the calcium lactate can be released from the particle in morethan about 30 minutes or more than about 45 minutes. In another aspect,the period of sustained dissolution is over a time scale of hours, forexample half of the calcium ion of the calcium lactate can be releasedin more than about 1 hour, more than 1.5 hours, more than about 2 hours,more than about 4 hours, more than about 8 hours, or more than about 12hours. In a further aspect, the period of sustained dissolution is overa period of one day or two days.

The respirable dry particles can be characterized by the crystalline andamorphous content of the particles. The respirable dry particles cancomprise a mixture of amorphous and crystalline content, in which themonovalent metal cation salt, e.g., sodium salt and/or potassium salt,is substantially in the crystalline phase. As described herein, therespirable dry particles can further comprise an excipient, such asleucine, maltodextrin or mannitol, and/or a pharmaceutically activeagent. The excipient and pharmaceutically active agent can independentlybe crystalline or amorphous or present in a combination of these forms.In some embodiments, the excipient is amorphous or predominatelyamorphous. In some embodiments, the respirable dry particles aresubstantially crystalline.

This provides several advantages. For example, the crystalline phase(e.g., crystalline sodium chloride) can contribute to the stability ofthe dry particle in the dry state and to the dispersibilitycharacteristics, whereas the amorphous phase (e.g., amorphous activeagent and/or excipient) can facilitate rapid water uptake anddissolution of the particle upon deposition in the respiratory tract. Itis particularly advantageous when salts with relatively high aqueoussolubilities (such as sodium chloride) that are present in the dryparticles are in a crystalline state and when salts with relatively lowaqueous solubilities (such as calcium citrate) are present in the dryparticles in an amorphous state.

The amorphous phase can be characterized by a high glass transitiontemperature (T_(g)), such as a T_(g) of at least 100° C., at least 110°C., 120° C., at least 125° C., at least 130° C., at least 135° C., atleast 140° C., between 120° C. and 200° C., between 125° C. and 200° C.,between 130° C. and 200° C., between 120° C. and 190° C., between 125°C. and 190° C., between 130° C. and 190° C., between 120° C. and 180°C., between 125° C. and 180° C., or between 130° C. and 180° C.Alternatively, the amorphous phase can be characterized by a high T_(g)such as at least 80° C. or at least 90° C.

In some embodiments, the respirable dry particles contain an excipientand/or active agent rich amorphous phase and a monovalent salt (sodiumsalt, potassium salt) crystalline phase and the ratio of amorphous phaseto crystalline phase (w:w) is about 5:95 to about 95:5, about 5:95 toabout 10:90, about 10:90 to about 20:80, about 20:80 to about 30:70,about 30:70 to about 40:60, about 40:60 to about 50:50; about 50:50 toabout 60:40, about 60:40 to about 70:30, about 70:30 to about 80:20, orabout 90:10 to about 95:5. In other embodiments, the respirable dryparticles contain an amorphous phase and a monovalent salt crystallinephase and the ratio of amorphous phase to particle by weight (w:w) isabout 5:95 to about 95:5, about 5:95 to about 10:90, about 10:90 toabout 20:80, about 20:80 to about 30:70, about 30:70 to about 40:60,about 40:60 to about 50:50; about 50:50 to about 60:40, about 60:40 toabout 70:30, about 70:30 to about 80:20, or about 90:10 to about 95:5.In other embodiments, the respirable dry particles contain an amorphousphase and a monovalent salt crystalline phase and the ratio ofcrystalline phase to particle by weight (w:w) is about 5:95 to about95:5, about 5:95 to about 10:90, about 10:90 to about 20:80, about 20:80to about 30:70, about 30:70 to about 40:60, about 40:60 to about 50:50;about 50:50 to about 60:40, about 60:40 to about 70:30, about 70:30 toabout 80:20, or about 90:10 to about 95:5.

In addition to any of the features and properties described herein, inany combination, the respirable dry particles can have a heat ofsolution that is not highly exothermic. Preferably, the heat of solutionis determined using the ionic liquid of a simulated lung fluid (e.g., asdescribed in Moss, O. R. 1979. Simulants of lung interstitial fluid.Health Phys. 36, 447-448; or in Sun, G. 2001. Oxidative interactions ofsynthetic lung epithelial lining fluid with metal-containing particulatematter. Am J Physiol Lung Cell Mol Physiol. 281, L807-L815) at pH 7.4and 37° C. in an isothermal calorimeter. For example, the respirable dryparticles can have a heat of solution that is less exothermic than theheat of solution of calcium chloride dihydrate, e.g., have a heat ofsolution that is greater than about −10 kcal/mol, greater than about −9kcal/mol, greater than about −8 kcal/mol, greater than about −7kcal/mol, greater than about −6 kcal/mol, greater than about −5kcal/mol, greater than about −4 kcal/mol, greater than about −3kcal/mol, greater than about −2 kcal/mol, greater than about −1 kcal/molor about −10 kcal/mol to about 10 kcal/mol.

The respirable dry powders and dry particles are characterized by a highemitted dose (e.g., CEPM of at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%) from a dry powderinhaler when a total inhalation energy of less than about 2 Joules orless than about 1 Joule, or less than about 0.8 Joule, or less thanabout 0.5 Joule, or less than about 0.3 Joule is applied to the drypowder inhaler. The dry powder can fill the unit dose container, or theunit dose container can be at least 10% full, at least 20% full, atleast 30% full, at least 40% full, at least 50% full, at least 60% full,at least 70% full, at least 80% full, or at least 90% full. The unitdose container can be a capsule (e.g., size 000, 00, 0E, 0, 1, 2, 3, and4, with respective volumetric capacities of 1.37 ml, 950 μl, 770 μl, 680μl, 480 μl, 360 μl, 270 μl, and 200 μl).

Healthy adult populations are predicted to be able to achieve inhalationenergies ranging from 2.9 Joules for comfortable inhalations to 22Joules for maximum inhalations by using values of peak inspiratory flowrate (PIFR) measured by Clarke et al. (Journal of Aerosol Med, 6(2), p.99-110, 1993) for the flow rate Q from two inhaler resistances of 0.02and 0.055 kPa1/2/LPM, with a inhalation volume of 2 L based on both FDAguidance documents for dry powder inhalers and on the work of Tiddens etal. (Journal of Aerosol Med, 19(4), p. 456-465, 2006) who found adultsaveraging 2.2 L inhaled volume through a variety of DPIs.

Mild, moderate and severe adult COPD patients are predicted to be ableto achieve maximum inhalation energies of 5.1 to 21 Joules, 5.2 to 19Joules, and 2.3 to 18 Joules respectively. This is again based on usingmeasured PIFR values for the flow rate Q in the equation for inhalationenergy. The PIFR achievable for each group is a function of the inhalerresistance that is being inhaled through. The work of Broeders et al.(Eur Respir J, 18, p. 780-783, 2001) was used to predict maximum andminimum achievable PIFR through 2 dry powder inhalers of resistances0.021 and 0.032 kPa1/2/LPM for each.

Similarly, adult asthmatic patients are predicted to be able to achievemaximum inhalation energies of 7.4 to 21 Joules based on the sameassumptions as the COPD population and PIFR data from Broeders et al.

Healthy adults and children, COPD patients, asthmatic patients ages 5and above, and CF patients, for example, are capable of providingsufficient inhalation energy to empty and disperse the dry powderformulations of the invention.

An advantage of aspects of the invention is the production of powdersthat disperse well across a wide range of flow rates and are relativelyflow rate independent. In certain aspects, the dry particles and powdersof the invention enable the use of a simple, passive DPI for a widepatient population.

In preferred aspects, the respirable dry powder comprises respirable dryparticles that characterized by:

1. VMGD at 1 bar as measured using a HELOS/RODOS system between 0.5microns and 10 microns, preferably between 1 microns and 7 microns,between 1 microns and 5 microns, or between 1 microns and 3 microns;

2. 1 bar/4 bar of 1.6 or less, preferably less than 1.5, less than 1.4,less than 1.3, less than 1.2 or less than 1.1; and

3. tap density of about 0.4 g/cm³ to about 1.2 g/cm³, 0.5 g/cm³ to about1.0 g/cm³, preferably between about 0.6 g/cm³ and about 0.9 g/cm³.

In other preferred aspects, the respirable dry powder comprisesrespirable dry particles that are characterized by:

1. VMGD at 1 bar as measured using a HELOS/RODOS system between 0.5microns and 10 microns, preferably between 1 microns and 7 microns,between 1 microns and 5 microns, or between 1 microns and 3 microns;

2. 1 bar/4 bar of 1.6 or less, preferably less than 1.5, less than 1.4,less than 1.3, less than 1.2 or less than 1.1; and

3. MMAD between 0.5 and 6.0, between 1.0 and 5.0 or between 1.0 and 3.0.

In other preferred aspects, the respirable dry powder comprisesrespirable dry particles that are characterized by:

1. VMGD at 1 bar as measured using a HELOS/RODOS system between 0.5microns and 10 microns, preferably between 1 microns and 7 microns,between 1 microns and 5 microns, or between 1 microns and 3 microns;

2. 1 bar/4 bar of 1.6 or less, preferably less than 1.5, less than 1.4,less than 1.3, less than 1.2 or less than 1.1; and

3. FPF_TD<5.0 μm of at least 30%, at least 40%, at least 50% or at least60%.

In other preferred aspects, the respirable dry powder comprisesrespirable dry particles that are characterized by:

1. VMGD at 1 bar as measured using a HELOS/RODOS system; less than 10microns, between 0.5 microns and 10 microns, between 1 microns and 7microns, preferably between 1 microns and 5 microns, or between 1microns and 3 microns;

2. 1 bar/4 bar of 1.6 or less, preferably less than 1.5, less than 1.4,less than 1.3, less than 1.2 or less than 1.1; and

3. Hausner Ratio greater than 1.5, greater than 1.8, or greater than2.1.

In other preferred aspects, the respirable dry powder comprisesrespirable dry particles that are characterized by:

1. tap density of about 0.4 g/cm³ to about 1.2 g/cm³, 0.5 g/cm³ to about1.0 g/cm³, preferably between about 0.6 g/cm³ and about 0.9 g/cm³.

2. FPF_TD<5.0 μm of at least 30%, at least 40%, at least 50% or at least60%.

3. Hausner Ratio greater than 1.5, greater than 1.8, or greater than2.1.

For each of the preferred embodiments described, the respirable dryparticles described herein contain a monovalent salt; such as a sodiumsalt and/or a potassium salt, e.g., sodium chloride, sodium citrate,sodium lactate, sodium sulfate, potassium chloride, potassium citrate,or any combinations thereof, in an amount between about 1% and about20%, between about 3% and about 20%, between about 20% and about 60%, orbetween about 60% and about 99%. The preferred embodiments may furthercontain:

-   -   (a) an active agent, such as a LABA (e.g., formoterol,        salmeterol), a short-acting beta agonist (e.g., albuterol), a        corticosteroid (e.g., fluticasone), a LAMA (e.g., tiotropium),        an antibiotic (e.g., levofloxacin, tobramycin), antibodies        (e.g., therapeutic antibodies), hormones (e.g. insulin),        cytokines, growth factors and combinations thereof. When the dry        powders are intended for treatment of CF, preferred additional        therapeutic agents are short-acting beta agonists (e.g.,        albuterol), antibiotics (e.g., levofloxacin), recombinant human        deoxyribonuclease I (e.g., dornase alfa, also known as DNase),        sodium channel blockers (e.g., amiloride), and combinations        thereof, in an amount between about 0.01% and about 10%, between        about 10% and about 50%, or between about 50% and about 99.9,        and further may contain,    -   (b) an excipient, such as leucine, maltodextrin, mannitol or any        combination thereof, or the like, can be present in an amount of        about 80% or less or about 50% or less or about 20% or less by        weight of the dry particle.

The respirable dry particles and dry powders described herein aresuitable for inhalation therapies. The respirable dry particles may befabricated with the appropriate material, surface roughness, diameterand density for localized delivery to selected regions of therespiratory system such as the deep lung or upper or central airways.For example, higher density or larger respirable dry particles may beused for upper airway delivery, or a mixture of varying size respirabledry particles in a sample, provided with the same or a differentformulation, may be administered to target different regions of the lungin one administration.

Because the respirable dry powders and respirable dry particlesdescribed herein contain salts, they may be hygroscopic. Accordingly itis desirable to store or maintain the respirable dry powders andrespirable dry particles under conditions to prevent hydration of thepowders. For example, if it is desirable to prevent hydration, therelative humidity of the storage environment should be less than 75%,less than 60%, less than 50%, less than 40%, less than 35%, less than30%, less than 25%, less than 20%, less than 15%, less than 10%, or lessthan 5% humidity. In other embodiments, the storage environment shouldbe between 20% to 40%, between 25% to 35%, about 30%, between 10% to20%, or about 15% humidity. The respirable dry powders and respirabledry particles can be packaged (e.g., in sealed capsules, blisters,vials) under these conditions.

In preferred embodiments, the respirable dry powders or respirable dryparticles of the invention possess aerosol characteristics that permiteffective delivery of the respirable dry particles to the respiratorysystem without the use of propellants.

The dry particles of the invention can be blended with an activeingredient or co-formulated with an active ingredient to maintain thecharacteristic high dispersibility of the dry particles and dry powdersof the invention.

Methods for Preparing Dry Powders and Dry Particles

The respirable dry particles and dry powders can be prepared using anysuitable method. Many suitable methods for preparing respirable drypowders and particles are conventional in the art, and include singleand double emulsion solvent evaporation, spray drying, spray freezedrying, milling (e.g., jet milling), blending, solvent extraction,solvent evaporation, phase separation, simple and complex coacervation,interfacial polymerization, suitable methods that involve the use ofsupercritical carbon dioxide (CO₂), sonocrystalliztion, nanoparticleaggregate formation and other suitable methods, including combinationsthereof. Respirable dry particles can be made using methods for makingmicrospheres or microcapsules known in the art. These methods can beemployed under conditions that result in the formation of respirable dryparticles with desired aerodynamic properties (e.g., aerodynamicdiameter and geometric diameter). If desired, respirable dry particleswith desired properties, such as size and density, can be selected usingsuitable methods, such as sieving.

The respirable dry particles are preferably spray dried. Suitable spraydrying techniques are described, for example, by K. Masters in “SprayDrying Handbook”, John Wiley & Sons, New York (1984). Generally, duringspray drying, heat from a hot gas such as heated air or nitrogen is usedto evaporate a solvent from droplets formed by atomizing a continuousliquid feed. If desired, the spray drying or other instruments, e.g.,jet milling instrument, used to prepare the dry particles can include aninline geometric particle sizer that determines a geometric diameter ofthe respirable dry particles as they are being produced, and/or aninline aerodynamic particle sizer that determines the aerodynamicdiameter of the respirable dry particles as they are being produced.

For spray drying, solutions, emulsions or suspensions that contain thecomponents of the dry particles to be produced in a suitable solvent(e.g., aqueous solvent, organic solvent, aqueous-organic mixture oremulsion) are distributed to a drying vessel via an atomization device.For example, a nozzle or a rotary atomizer may be used to distribute thesolution or suspension to the drying vessel. For example, a rotaryatomizer having a 4- or 24-vaned wheel may be used. Examples of suitablespray dryers that can be outfitted with either a rotary atomizer or anozzle, include, Mobile Minor Spray Dryer or the Model PSD-1, bothmanufactured by GEA Group (Niro, Denmark). Actual spray dryingconditions will vary depending, in part, on the composition of the spraydrying solution or suspension and material flow rates. The person ofordinary skill will be able to determine appropriate conditions based onthe compositions of the solution, emulsion or suspension to be spraydried, the desired particle properties and other factors. In general,the inlet temperature to the spray dryer is about 90° C. to about 300°C., and preferably is about 220° C. to about 285° C. The spray dryeroutlet temperature will vary depending upon such factors as the feedtemperature and the properties of the materials being dried. Generally,the outlet temperature is about 50° C. to about 150° C., preferablyabout 90° C. to about 120° C., or about 98° C. to about 108° C. Ifdesired, the respirable dry particles that are produced can befractionated by volumetric size, for example, using a sieve, orfractioned by aerodynamic size, for example, using a cyclone, and/orfurther separated according to density using techniques known to thoseof skill in the art.

To prepare the respirable dry particles of the invention, generally, asolution, emulsion or suspension that contains the desired components ofthe dry powder (i.e., a feed stock) is prepared and spray dried undersuitable conditions. Preferably, the dissolved or suspended solidsconcentration in the feed stock is at least about 1 g/L, at least about2 g/L, at least about 5 g/L, at least about 10 g/L, at least about 15g/L, at least about 20 g/L, at least about 30 g/L, at least about 40g/L, at least about 50 g/L, at least about 60 g/L, at least about 70g/L, at least about 80 g/L, at least about 90 g/L, or at least about 100g/L. The feed stock can be provided by preparing a single solution orsuspension by dissolving or suspending suitable components (e.g., salts,excipients, other active ingredients) in a suitable solvent. Thesolvent, emulsion or suspension can be prepared using any suitablemethods, such as bulk mixing of dry and/or liquid components or staticmixing of liquid components to form a combination. For example, ahydrophilic component (e.g., an aqueous solution) and a hydrophobiccomponent (e.g., an organic solution) can be combined using a staticmixer to form a combination. The combination can then be atomized toproduce droplets, which are dried to form respirable dry particles.Preferably, the atomizing step is performed immediately after thecomponents are combined in the static mixer.

The feed stock, or components of the feed stock, can be prepared usingany suitable solvent, such as an organic solvent, an aqueous solvent ormixtures thereof. Suitable organic solvents that can be employed includebut are not limited to alcohols such as, for example, ethanol, methanol,propanol, isopropanol, butanols, and others. Other organic solventsinclude but are not limited to perfluorocarbons, dichloromethane,chloroform, ether, ethyl acetate, methyl tert-butyl ether and others.Co-solvents that can be employed include an aqueous solvent and anorganic solvent, such as, but not limited to, the organic solvents asdescribed above. Aqueous solvents include water and buffered solutions.

The feed stock or components of the feed stock can have any desired pH,viscosity or other properties. If desired, a pH buffer can be added tothe solvent or co-solvent or to the formed mixture. Generally, the pH ofthe mixture ranges from about 3 to about 8.

Respirable dry particles and dry powders can be fabricated and thenseparated, for example, by filtration or centrifugation by means of acyclone, to provide a particle sample with a preselected sizedistribution. For example, greater than about 30%, greater than about40%, greater than about 50%, greater than about 60%, greater than about70%, greater than about 80%, or greater than about 90% of the respirabledry particles in a sample can have a diameter within a selected range.The selected range within which a certain percentage of the respirabledry particles fall can be, for example, any of the size ranges describedherein, such as between about 0.1 to about 3 microns VMGD, or between0.5 to about 5 micron VMGD.

The invention also relates to respirable dry powders or respirable dryparticles produced by preparing a feedstock solution, emulsion orsuspension and spray drying the feedstock according to the methodsdescribed herein, and to the methods described herein. The feedstock canbe prepared, for example, using (a) monovalent salt, such as sodiumchloride or potassium chloride, in an amount of about 1% to 100% byweight (e.g., of total solutes used for preparing the feedstock), anexcipient, such as leucine, in an amount of about 0% to 99% by weight(e.g., of total solutes used for preparing the feedstock), andoptionally a pharmaceutically active agent in an amount of about 0.001%to 99% by weight (e.g., of total solutes used for preparing thefeedstock), and one or more suitable solvents for dissolution of thesolute and formation of the feedstock.

Any suitable method can be used for mixing the solutes and solvents toprepare feedstocks (e.g., static mixing, bulk mixing). If desired,additional components that cause or facilitate the mixing can beincluded in the feedstock. For example, carbon dioxide produces fizzingor effervescence and thus can serve to promote physical mixing of thesolute and solvents. Various salts of carbonate or bicarbonate canpromote the same effect that carbon dioxide produces and, therefore, canbe used in preparation of the feedstocks of the invention.

In an embodiment, the respirable dry powders or respirable dry particlesof the invention can be produced through an ion exchange reaction. Incertain embodiments of the invention, two saturated or sub-saturatedsolutions are fed into a static mixer in order to obtain a saturated orsupersaturated solution post-static mixing. Preferably, the post-mixedsolution is supersaturated. The post-mixed solution may besupersaturated in all components or supersaturated in one, two, or threeof the components.

The two solutions may be aqueous or organic, but are preferablysubstantially aqueous. When the active agent is dissolved in an organicsolvent, then one feed solution may be organic while the other one maybe aqueous, or both feed solutions may be organic. The post-staticmixing solution is then fed into the atomizing unit of a spray dryer. Ina preferable embodiment, the post-static mixing solution is immediatelyfed into the atomizer unit. Some examples of an atomizer unit include atwo-fluid nozzle, a rotary atomizer, or a pressure nozzle. Preferably,the atomizer unit is a two-fluid nozzle. In one embodiment, thetwo-fluid nozzle is an internally mixing nozzle, meaning that the gasimpinges on the liquid feed before exiting to most outward orifice. Inanother embodiment, the two-fluid nozzle is an externally mixing nozzle,meaning that the gas impinges on the liquid feed after exiting the mostoutward orifice.

The diameter of the respirable dry particles, for example, their VMGD,can be measured using an electrical zone sensing instrument such as aMultisizer IIe, (Coulter Electronic, Luton, Beds, England), or a laserdiffraction instrument such as a HELOS system (Sympatec, Princeton,N.J.) or a Mastersizer system (Malvern, Worcestershire, UK). Otherinstruments for measuring particle geometric diameter are well known inthe art. The diameter of respirable dry particles in a sample will rangedepending upon factors such as particle composition and methods ofsynthesis. The distribution of size of respirable dry particles in asample can be selected to permit optimal deposition within targetedsites within the respiratory system.

Experimentally, aerodynamic diameter can be determined using time offlight (TOF) measurements. For example, an instrument such as theAerosol Particle Sizer (APS) Spectrometer (TSI Inc., Shoreview, MNcan beused to measure aerodynamic diameter. The APS measures the time takenfor individual respirable dry particles to pass between two fixed laserbeams.

Aerodynamic diameter also can be experimentally determined directlyusing conventional gravitational settling methods, in which the timerequired for a sample of respirable dry particles to settle a certaindistance is measured. Indirect methods for measuring the mass medianaerodynamic diameter include the Andersen Cascade Impactor (ACI) and themulti-stage liquid impinger (MSLI) methods. The methods and instrumentsfor measuring particle aerodynamic diameter are well known in the art.

Tap density is a measure of the envelope mass density characterizing aparticle. The envelope mass density of a particle of a statisticallyisotropic shape is defined as the mass of the particle divided by theminimum sphere envelope volume within which it can be enclosed. Featureswhich can contribute to low tap density include irregular surfacetexture, high particle cohesiveness and porous structure. Tap densitycan be measured by using instruments known to those skilled in the artsuch as the Dual Platform Microprocessor Controlled Tap Density Tester(Vankel, N.C.), a GeoPyc™ instrument (Micrometrics Instrument Corp.,Norcross, Ga.), or SOTAX Tap Density Tester model TD2 (SOTAX Corp.,Horsham, Pa.). Tap density can be determined using the method of USPBulk Density and Tapped Density, United States Pharmacopeia convention,Rockville, Md., 10^(th) Supplement, 4950-4951, 1999.

Fine particle fraction can be used as one way to characterize theaerosol performance of a dispersed powder. Fine particle fractiondescribes the size distribution of airborne respirable dry particles.Gravimetric analysis, using a Cascade Impactor, is one method ofmeasuring the size distribution, or fine particle fraction, of airbornerespirable dry particles. The ACI is an eight-stage Impactor that canseparate aerosols into nine distinct fractions based on aerodynamicsize. The size cutoffs of each stage are dependent upon the flow rate atwhich the ACI is operated. The ACI is made up of multiple stagesconsisting of a series of nozzles (i.e., a jet plate) and an impactionsurface (i.e., an impaction disc). At each stage an aerosol streampasses through the nozzles and impinges upon the surface. Respirable dryparticles in the aerosol stream with a large enough inertia will impactupon the plate. Smaller respirable dry particles that do not have enoughinertia to impact on the plate will remain in the aerosol stream and becarried to the next stage. Each successive stage of the ACI has a higheraerosol velocity in the nozzles so that smaller respirable dry particlescan be collected at each successive stage.

If desired, a two-stage collapsed ACI can also be used to measure fineparticle fraction. The two-stage collapsed ACI consists of only the toptwo stages 0 and 2 of the eight-stage ACI, as well as the finalcollection filter, and allows for the collection of two separate powderfractions. Specifically, a two-stage collapsed ACI is calibrated so thatthe fraction of powder that is collected on stage two is composed ofrespirable dry particles that have an aerodynamic diameter of less than5.6 microns and greater than 3.4 microns. The fraction of powder passingstage two and depositing on the final collection filter is thus composedof respirable dry particles having an aerodynamic diameter of less than3.4 microns. The airflow at such a calibration is approximately 60L/min. The FPF(<5.6) has been demonstrated to correlate to the fractionof the powder that is able to reach the lungs of the patient, while theFPF(<3.4) has been demonstrated to correlate to the fraction of thepowder that reaches the deep lung of a patient. These correlationsprovide a quantitative indicator that can be used for particleoptimization.

The FPF(<5.6) has been demonstrated to correlate to the fraction of thepowder that is able to make it into the lung of the patient, while theFPF(<3.4) has been demonstrated to correlate to the fraction of thepowder that reaches the deep lung of a patient. These correlationsprovide a quantitative indicator that can be used for particleoptimization.

An ACI can be used to approximate the emitted dose, which herein iscalled gravimetric recovered dose and analytical recovered dose.“Gravimetric recovered dose” is defined as the ratio of the powderweighed on all stage filters of the ACI to the nominal dose. “Analyticalrecovered dose” is defined as the ratio of the powder recovered fromrinsing and analyzing all stages, all stage filters, and the inductionport of the ACI to the nominal dose. The FPF_TD(<5.0) is the ratio ofthe interpolated amount of powder depositing below 5.0 μm on the ACI tothe nominal dose. The FPF_RD(<5.0) is the ratio of the interpolatedamount of powder depositing below 5.0 μm on the ACI to either thegravimetric recovered dose or the analytical recovered dose.

Another way to approximate emitted dose is to determine how much powderleaves its container, e.g. capture or blister, upon actuation of a drypowder inhaler (DPI). This takes into account the percentage leaving thecapsule, but does not take into account any powder depositing on theDPI. The emitted powder mass is the difference in the weight of thecapsule with the dose before inhaler actuation and the weight of thecapsule after inhaler actuation. This measurement can be called thecapsule emitted powder mass (CEPM) or sometimes termed “shot-weight”.

A Multi-Stage Liquid Impinger (MSLI) is another device that can be usedto measure fine particle fraction. The MSLI operates on the sameprinciples as the ACI, although instead of eight stages, MSLI has five.Additionally, each MSLI stage consists of an ethanol-wetted glass fritinstead of a solid plate. The wetted stage is used to prevent particlebounce and re-entrainment, which can occur when using the ACI.

The geometric particle size distribution can be measured for therespirable dry powder after being emitted from a dry powder inhaler(DPI) by use of a laser diffraction instrument such as the MalvernSpraytec. With the inhaler adapter in the close-bench configuration, anairtight seal is made to the DPI, causing the outlet aerosol to passperpendicularly through the laser beam as an internal flow. In this way,known flow rates can be drawn through the DPI by vacuum pressure toempty the DPI. The resulting geometric particle size distribution of theaerosol is measured by the photodetectors with samples typically takenat 1000 Hz for the duration of the inhalation and the DV50, GSD, FPF<5.0μm measured and averaged over the duration of the inhalation.

The invention also relates to a respirable dry powder or respirable dryparticles produced using any of the methods described herein.

The respirable dry particles of the invention can also be characterizedby the physicochemical stability of the salts or the excipients that therespirable dry particles comprise. The physicochemical stability of theconstituent salts can affect important characteristics of the respirableparticles including shelf-life, proper storage conditions, acceptableenvironments for administration, biological compatibility, andeffectiveness of the salts. Chemical stability can be assessed usingtechniques well known in the art. One example of a technique that can beused to assess chemical stability is reverse phase high performanceliquid chromatography (RP-HPLC). Respirable dry particles of theinvention include salts that are generally stable over a long periodtime.

If desired, the respirable dry particles and dry powders describedherein can be further processed to increase stability. An importantcharacteristic of pharmaceutical dry powders is whether they are stableat different temperature and humidity conditions. Unstable powders willabsorb moisture from the environment and agglomerate, thus alteringparticle size distribution of the powder.

Excipients, such as maltodextrin, may be used to create more stableparticles and powders. For example, maltodextrin may act as an amorphousphase stabilizer and inhibit the components from converting from anamorphous to crystalline state. Alternatively, a post-processing step tohelp the particles through the crystallization process in a controlledway (e.g., on the product filter at elevated humidity) can be employedwith the resultant powder potentially being further processed to restoretheir dispersibility if agglomerates formed during the crystallizationprocess, such as by passing the particles through a cyclone to breakapart the agglomerates. Another possible approach is to optimize aroundformulation or process conditions that lead to manufacturing particlesthat are more crystalline and therefore more stable. Another approach isto use different excipients, or different levels of current excipientsto attempt to manufacture more stable forms of the salts.

Therapeutic Use and Methods

The respirable dry powders and respirable dry particles of the presentinvention are for administration to the respiratory tract.Administration to the respiratory tract can be for local activity of thedelivered pharmaceutically active agent or for systemic activity. Forexample, the respirable dry powders can be administered to the nasalcavity or upper airway to provide, for example, anti-inflammatory,anti-viral, or anti-bacterial activity to the nasal cavity or upperairway. The respirable dry powders can be administered to the deep lungto provide local activity in the lung or for absorption into thesystemic circulation. Systemic delivery of certain pharmaceuticallyactive agents via the lung is particularly advantageous for agents thatundergo substantial first pass metabolism (e.g., in the liver) followingoral administration.

The respirable dry powders and respirable dry particles of the presentinvention may also be administered to the buccal cavity. Administrationto the buccal cavity can be for local activity of the deliveredpharmaceutically active agent or for systemic activity. For exaple, therespirable dry powders can be administered to the buccal cavity toprovide, for example, anti-inflammatory, anti-viral, or anti-bacterialactivity to the buccal cavity.

The dry powders and dry particles of the invention can be administeredto a subject in need thereof for systemic delivery of a pharmaceuticallyactive agent, such as to treat an infectious disease or metabolicdisease.

The dry powders and dry particles of the invention can be administeredto a subject in need thereof for the treatment of respiratory (e.g.,pulmonary) diseases, such as respiratory syncytial virus infection,idiopathic fibrosis, alpha-1 antitrypsin deficiency, asthma, airwayhyperresponsiveness, seasonal allergic allergy, brochiectasis, chronicbronchitis, emphysema, chronic obstructive pulmonary disease, cysticfibrosis and the like, and for the treatment and/or prevention of acuteexacerbations of these chronic diseases, such as exacerbations caused byviral infections (e.g., influenza virus, parainfluenza virus,respiratory syncytial virus, rhinovirus, adenovirus, metapneumovirus,coxsackie virus, echo virus, corona virus, herpes virus,cytomegalovirus, and the like), bacterial infections (e.g.,Streptococcus pneumoniae, which is commonly referred to as pneumococcus,Staphylococcus aureus, Burkholderis ssp., Streptococcus agalactiae,Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiellapneumoniae, Escherichia coli, Pseudomonas aeruginosa, Moraxellacatarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Legionellapneumophila, Serratia marcescens, Mycobacterium tuberculosis, Bordetellapertussis, and the like), fungal infections (e.g., Histoplasmacapsulatum, Cryptococcus neoformans, Pneumocystis jiroveci, Coccidioidesimmitis, and the like) or parasitic infections (e.g., Toxoplasma gondii,Strongyloides stercoralis, and the like), or environmental allergens andirritants (e.g., aeroallergens, including pollen and cat dander,airborne particulates, and the like).

The dry powders and dry particles of the invention can be administeredto a subject in need thereof for the treatment and/or prevention and/orreducing contagion of infectious diseases of the respiratory tract, suchas pneumonia (including community-acquired pneumonia, nosocomialpneumonia (hospital-acquired pneumonia, HAP; health-care associatedpneumonia, HCAP), ventilator-associated pneumonia (VAP)),ventilator-associated tracheobronchitis (VAT), bronchitis, croup (e.g.,postintubation croup, and infectious croup), tuberculosis, influenza,common cold, and viral infections (e.g., influenza virus, parainfluenzavirus, respiratory syncytial virus, rhinovirus, adenovirus,metapneumovirus, coxsackie virus, echo virus, corona virus, herpesvirus, cytomegalovirus, and the like), bacterial infections (e.g.,Streptococcus pneumoniae, which is commonly referred to as pneumococcus,Staphylococcus aureus, Streptococcus agalactiae, Haemophilus influenzae,Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli,Pseudomonas aeruginosa, Moraxella catarrhalis, Chlamydophila pneumoniae,Mycoplasma pneumoniae, Legionella pneumophila, Serratia marcescens,Mycobacterium tuberculosis, Bordetella pertussis, and the like), fungalinfections (e.g., Histoplasma capsulatum, Cryptococcus neoformans,Pneumocystis jiroveci, Coccidioides immitis, and the like) or parasiticinfections (e.g., Toxoplasma gondii, Strongyloides stercoralis, and thelike), or environmental allergens and irritants (e.g., aeroallergens,airborne particulates, and the like).

In some aspects, the invention provides a method for treating apulmonary diseases, such as asthma, airway hyperresponsiveness, seasonalallergic allergy, bronchiectasis, chronic bronchitis, emphysema, chronicobstructive pulmonary disease, cystic fibrosis and the like, comprisingadministering to the respiratory tract of a subject in need thereof aneffective amount of respirable dry particles or dry powder, as describedherein.

In other aspects, the invention provides a method for the treatment orprevention of acute exacerbations of a chronic pulmonary disease, suchas asthma, airway hyperresponsiveness, seasonal allergic allergy,bronchiectasis, chronic bronchitis, emphysema, chronic obstructivepulmonary disease, cystic fibrosis and the like, comprisingadministering to the respiratory tract of a subject in need thereof aneffective amount of respirable dry particles or dry powder, as describedherein.

In some aspects, the invention provides a method for the treatment orprevention of cardiovascular disease, auto-immune disorders, transplantrejections, autoimmune disorders, allergy-related asthma, infections,and cancer. For example, the invention provides a method for thetreatment or prevention of postmenopausal osteoporosis,cryopyrin-associated periodic syndromes (CAPS), paroxysmal nocturnalhemoglobinuria, psoriasis, rheumatoid arthritis, psoriatic arthritis,ankylosing spondylitis, multiple sclerosis, and macular degeneration.For example, dry powders or dry particles of the invention areco-formulated or blended with therapeutic antibodies as describedherein. The co-formulated or blended dry powders may then beadministered to a subject in need of therapy or prevention.

In certain aspects, the invention provides a method for the treatment orprevention of cancer such as acute myeloid leukemia, B cell leukemia,non-Hodgkin's lymphoma, breast cancer (e.g. with HER2/neuoverexpression), glioma, squamous cell carcinomas, colorectal carcinoma,anaplastic large cell lymphoma (ALCL), Hodgkin lymphoma, head and neckcancer, acute myelogenous leukemia (AML), melanoma, and chroniclymphocytic leukemia (CLL). Alternatively or in addition, the inventionprovides a method for the treatment or prevention of cancer byanti-angiogenic cancer therapy. For example, dry powders or dryparticles of the invention are co-formulated or blended with therapeuticantibodies as described herein. Therapeutic antibodies can becancer-specific antibodies, such as a humanized monoclonal antibody,e.g. gemtuzumab, alemtuzumab, trastuzumab, nimotuzumab, bevacizumab, ora chimeric monoclonal antibody, e.g. rituximab and cetuximab. Theco-formulated or blended dry powders may then be administered to asubject in need of therapy or prevention.

In certain aspects, the invention provides a method for the treatment orprevention of inflammation such as rheumatoid arthritis, Crohn'sdisease, ulcerative Colitis, acute rejection of kidney transplants,moderate-to-severe allergic asthma. For example, dry powders or dryparticles of the invention are co-formulated or blended with therapeuticantibodies as described herein. Therapeutic antibodies can beinflammation-specific antibodies, such as chimeric monoclonalantibodies, e.g. infliximab, basiliximab, humanized monoclonalantibodies, e.g. daclizumab, omalizumab, or human antibodies, e.g.adalimumab. The co-formulated or blended dry powders may then beadministered to a subject in need of therapy or prevention.

In certain aspects, the invention provides a method for the treatment orprevention of RSV infections in children. For example, dry powders ordry particles of the invention are co-formulated or blended withtherapeutic antibodies as described herein. Therapeutic antibodies canbe RSV infection-specific antibodies, such as the humanized monoclonalantibody palivizumab which inhibits an RSV fusion (F) protein. Theco-formulated or blended dry powders may then be administered to asubject in need of RSV infection therapy or prevention.

In certain aspects, the invention provides a method for the treatment orprevention of diabetes. For example, dry powders or dry particles of theinvention are co-formulated or blended with insulin as described herein.The co-formulated or blended dry powders may then be administered to asubject in need of insulin therapy or prevention.

The respirable dry particles and dry powders can be administered to therespiratory tract of a subject in need thereof using any suitablemethod, such as instillation techniques, and/or an inhalation device,such as a dry powder inhaler (DPI) or metered dose inhaler (MDI). Anumber of DPIs are available, such as, the inhalers disclosed is U.S.Pat. Nos. 4,995,385 and 4,069,819, Spinhaler® (Fisons, Loughborough,U.K.), Rotahalers®, Diskhaler® and Diskus® (GlaxoSmithKline, ResearchTriangle Technology Park, North Carolina), FlowCapss® (Hovione, Loures,Portugal), Inhalators® (Boehringer-Ingelheim, Germany), Aerolizer®(Novartis, Switzerland), high-resistance and low-resistacne RS-01(Plastiape, Italy), and others known to those skilled in the art.

Generally, inhalation devices (e.g., DPIs) are able to deliver a maximumamount of dry powder or dry particles in a single inhalation, which isrelated to the capacity of the blisters, capsules (e.g. size 000, 00,0E, 0, 1, 2, 3, and 4, with respective volumetric capacities of 1.37 ml,950 μl, 770 μl, 680 μl, 480 μl, 360 μl, 270 μl, and 200 μl) or othermeans that contain the dry particles or dry powders within the inhaler.Accordingly, delivery of a desired dose or effective amount may requiretwo or more inhalations. Preferably, each dose that is administered to asubject in need thereof contains an effective amount of respirable dryparticles or dry powder and is administered using no more than about 4inhalations. For example, each dose of respirable dry particles or drypowder can be administered in a single inhalation or 2, 3, or 4inhalations. The respirable dry particles and dry powders are preferablyadministered in a single, breath-activated step using a breath-activatedDPI. When this type of device is used, the energy of the subject'sinhalation both disperses the respirable dry particles and draws theminto the respiratory tract.

The respirable dry particles or dry powders can be delivered byinhalation to a desired area within the respiratory tract, as desired.It is well-known that particles with an aerodynamic diameter of about 1micron to about 3 microns, can be delivered to the deep lung. Largeraerodynamic diameters, for example, from about 3 microns to about 5microns can be delivered to the central and upper airways.

For dry powder inhalers, oral cavity deposition is dominated by inertialimpaction and so characterized by the aerosol's Stokes number (DeHaan etal. Journal of Aerosol Science, 35 (3), 309-331, 2003). For equivalentinhaler geometry, breathing pattern and oral cavity geometry, the Stokesnumber, and so the oral cavity deposition, is primarily affected by theaerodynamic size of the inhaled powder. Hence, factors which contributeto oral deposition of a powder include the size distribution of theindividual particles and the dispersibility of the powder. If the MMADof the individual particles is too large, e.g. above 5 um, then anincreasing percentage of powder will deposit in the oral cavity.Likewise, if a powder has poor dispersibility, it is an indication thatthe particles will leave the dry powder inhaler and enter the oralcavity as agglomerates. Agglomerated powder will perform aerodynamicallylike an individual particle as large as the agglomerate, therefore evenif the individual particles are small (e.g., MMAD of 5 microns or less),the size distribution of the inhaled powder may have an MMAD of greaterthan 5 μm, leading to enhanced oral cavity deposition.

Therefore, it is desirable to have a powder in which the particles aresmall (e.g., MMAD of 5 microns or less, e.g. between 1 to 5 microns),and are highly dispersible (e.g. 1 bar/4 bar or alternatively, 0.5 bar/4bar of 2.0, and preferably less than 1.5). More preferably, therespirable dry powder is comprised of respirable dry particles with anMMAD between 1 to 4 microns or 1 to 3 microns, and have a 1 bar/4 barless than 1.4, or less than 1.3, and more preferably less than 1.2.

The absolute geometric diameter of the particles measured at 1 bar usingthe HELOS system is not critical provided that the particle's envelopemass density is sufficient such that the MMAD is in one of the rangeslisted above, wherein MMAD is VMGD times the square root of the envelopemass density (MMAD=VMGD*sqrt(envelope mass density)). If it is desiredto deliver a high unit dose of pharmaceutically active agent using afixed volume dosing container, then, particles of higher envelop densityare desired. High envelope mass density allows for more mass of powderto be contained within the fixed volume dosing container. Preferableenvelope mass densities are greater than 0.1 g/cc, greater than 0.25g/cc, greater than 0.4 g/cc, greater than 0.5 g/cc, greater than 0.6g/cc, greater than 0.7 g/cc, and greater than 0.8 g/cc.

The respirable dry powders and particles of the invention can beemployed in compositions suitable for drug delivery via the respiratorysystem. For example, such compositions can include blends of therespirable dry particles of the invention and one or more other dryparticles or powders, such as dry particles or powders that containanother active agent, or that consist of or consist essentially of oneor more pharmaceutically acceptable excipients.

Respirable dry powders and dry particles suitable for use in the methodsof the invention can travel through the upper airways (i.e., theoropharynx and larynx), the lower airways, which include the tracheafollowed by bifurcations into the bronchi and bronchioli, and throughthe terminal bronchioli which in turn divide into respiratory bronchiolileading then to the ultimate respiratory zone, the alveoli or the deeplung. In one embodiment of the invention, most of the mass of respirabledry powders or particles deposit in the deep lung. In another embodimentof the invention, delivery is primarily to the central airways. Inanother embodiment, delivery is to the upper airways.

The respirable dry particles or dry powders of the invention can bedelivered by inhalation at various parts of the breathing cycle (e.g.,laminar flow at mid-breath). An advantage of the high dispersibility ofthe dry powders and dry particles of the invention is the ability totarget deposition in the respiratory tract. For example, breathcontrolled delivery of nebulized solutions is a recent development inliquid aerosol delivery (Dalby et al. in Inhalation Aerosols, edited byHickey 2007, p. 437). In this case, nebulized droplets are released onlyduring certain portions of the breathing cycle. For deep lung delivery,droplets are released in the beginning of the inhalation cycle, whilefor central airway deposition, they are released later in theinhalation.

The highly dispersible powders of the invention can provide advantagesfor targeting the timing of drug delivery in the breathing cycle andalso location in the human lung. Because the respirable dry powders ofthe invention can be dispersed rapidly, such as within a fraction of atypical inhalation maneuver, the timing of the powder dispersal can becontrolled to deliver an aerosol at specific times within theinhalation.

With a highly dispersible powder, the complete dose of aerosol can bedispersed at the beginning portion of the inhalation. While thepatient's inhalation flow rate ramps up to the peak inspiratory flowrate, a highly dispersible powder will begin to disperse already at thebeginning of the ramp up and could completely disperse a dose in thefirst portion of the inhalation. Since the air that is inhaled at thebeginning of the inhalation will ventilate deepest into the lungs,dispersing the most aerosol into the first part of the inhalation ispreferable for deep lung deposition. Similarly, for central deposition,dispersing the aerosol at a high concentration into the air which willventilate the central airways can be achieved by rapid dispersion of thedose near the mid to end of the inhalation. This can be accomplished bya number of mechanical and other means such as a switch operated bytime, pressure or flow rate which diverts the patient's inhaled air tothe powder to be dispersed only after the switch conditions are met.

Aerosol dosage, formulations and delivery systems may be selected for aparticular therapeutic application, as described, for example, in Gonda,I. “Aerosols for delivery of therapeutic and diagnostic agents to therespiratory tract,” in Critical Reviews in Therapeutic Drug CarrierSystems, 6: 273-313 (1990); and in Moren, “Aerosol Dosage Forms andFormulations,” in Aerosols in Medicine, Principles, Diagnosis andTherapy, Moren, et al., Eds., Esevier, Amsterdam (1985).

Suitable dosing to provide the desired therapeutic effect can bedetermined by a clinician based on the severity of the condition (e.g.,infection), overall well being of the subject and the subject'stolerance to respirable dry particles and dry powders and otherconsiderations. Based on these and other considerations, a clinician candetermine appropriate doses and intervals between doses. Generally,respirable dry particles and dry powders are administered once, twice orthree times a day, as needed.

If desired or indicated, the respirable dry particles and dry powdersdescribed herein can be administered with one or more other therapeuticagents. The other therapeutic agents can be administered by any suitableroute, such as orally, parenterally (e.g., intravenous, intraarterial,intramuscular, or subcutaneous injection), topically, by inhalation(e.g., intrabronchial, intranasal or oral inhalation, intranasal drops),rectally, vaginally, and the like. The respirable dry particles and drypowders can be administered before, substantially concurrently with, orsubsequent to administration of the other therapeutic agent. Preferably,the respirable dry particles and dry powders and the other therapeuticagent are administered so as to provide substantial overlap of theirpharmacologic activities.

Another advantage provided by the respirable dry powders and respirabledry particles described herein, is that dosing efficiency can beincreased as a result of hygroscopic growth of particles inside thelungs, due to particle moisture growth. The propensity of the partiallyamorphous, high salt compositions of the invention to take up water atelevated humidities can also be advantageous with respect to theirdeposition profiles in vivo. Due to their rapid water uptake at highhumidities, these powder formulations can undergo hygroscopic growth dothe absorbance of water from the humid air in the respiratory tract asthey transit into the lungs. This can result in an increase in theireffective aerodynamic diameters during transit into the lungs, whichwill further facilitate their deposition in the airways.

EXEMPLIFICATION Methods:

Geometric or Volume Diameter.

Volume median diameter (VMD) (x50), which may also be referred to asvolume median geometric diameter (VMGD) and Dv(50), was determined usinga laser diffraction technique. The equipment consisted of a HELOSdiffractometer and a RODOS dry powder disperser (Sympatec, Inc.,Princeton, N.J.). The RODOS disperser applies a shear force to a sampleof particles, controlled by the regulator pressure (typically set at 1.0bar with maximum orifice ring pressure) of the incoming compressed dryair. The pressure settings may be varied to vary the amount of energyused to disperse the powder. For example, the regulator pressure may bevaried from 0.2 bar to 4.0 bar. Powder sample is dispensed from amicrospatula into the RODOS funnel. The dispersed particles travelthrough a laser beam where the resulting diffracted light patternproduced is collected, typically using an R1 lens, by a series ofdetectors. The ensemble diffraction pattern is then translated into avolume-based particle size distribution using the Fraunhofer diffractionmodel, on the basis that smaller particles diffract light at largerangles. Using this method, geometric standard deviation (GSD) for thevolume mean geometric diameter was also determined.

Fine Particle Fraction.

The aerodynamic properties of the powders dispersed from an inhalerdevice were assessed with a Mk-II 1 ACFM Andersen Cascade Impactor(Copley Scientific Limited, Nottingham, UK). The instrument was run incontrolled environmental conditions of 18 to 25° C. and relativehumidity (RH) between 25 and 35%. The instrument consists of eightstages that separate aerosol particles based on inertial impaction. Ateach stage, the aerosol stream passes through a set of nozzles andimpinges on a corresponding impaction plate. Particles having smallenough inertia will continue with the aerosol stream to the next stage,while the remaining particles will impact upon the plate. At eachsuccessive stage, the aerosol passes through nozzles at a highervelocity and aerodynamically smaller particles are collected on theplate. After the aerosol passes through the final stage, a filtercollects the smallest particles that remain. Gravimetric or analyticalanalysis can then be performed to determine the particle sizedistribution.

The impaction technique utilized allowed for the collection of eightseparate powder fractions. The capsules (Capsugel, Greenwood, S.C.) werefilled with approximately 20, 40 or 50 mg powder and placed in ahand-held, breath-activated dry powder inhaler (DPI) device, the highresistance RS-01 DPI (Plastiape, Osnago, Italy). The capsule waspunctured and the powder was drawn through the cascade impactor operatedat a flow rate of 60.0 L/min for 2.0 seconds. At this flow rate, thecalibrated cut-off diameters for the eight stages are 8.6, 6.5, 4.4,3.3, 2.0, 1.1, 0.5 and 0.3 microns. The fractions were collected byplacing filters in the apparatus and determining the amount of powderthat impinged on them by gravimetric and/or analytical measurements. Thefine particle fraction of the total dose of powder (FPF_TD) less than orequal to an effective cut-off aerodynamic diameter was calculated bydividing the powder mass recovered from the desired stages of theimpactor by the total particle mass in the capsule. Results are reportedas the fine particle fraction of less than 4.4 microns (FPF<4.4microns), as well as mass median aerodynamic diameter (MMAD) and GSDcalculated from the FPF trend across stages. The fine particle fractioncan alternatively be calculated relative to the recovered or emitteddose of powder by dividing the powder mass recovered from the desiredstages of the impactor by the total powder mass recovered.

If desired, a two-stage collapsed ACI can also be used to measure fineparticle fraction. The two-stage collapsed ACI consists of only stages 0and 2, and the collection filter, all from the eight-stage ACI, andallows for the collection of two separate powder fractions.Specifically, a two-stage collapsed ACI is calibrated so that thefraction of powder that is collected on stage two is composed ofrespirable dry particles that have an aerodynamic diameter of less than5.6 microns and greater than 3.4 microns. The fraction of powder passingstage two and depositing on a collection filter (stage F) is thuscomposed of respirable dry particles having an aerodynamic diameter ofless than 3.4 microns. The airflow at such a calibration isapproximately 60 L/min.

Tap Density.

Tap density was measured using a modified USP method requiring smallerpowder quantities by following USP <616> with the substitution of a 1.5cc microcentrifuge tube (Eppendorf AG, Hamburg, Germany) or a 0.3 ccsection of a disposable serological polystyrene micropipette (GrenierBio-One, Monroe, N.C.) with polyethylene caps (Kimble Chase, Vineland,N.J.) to cap both ends and hold the powder within the pipette section.Instruments for measuring tap density, known to those skilled in theart, include but are not limited to the Dual Platform MicroprocessorControlled Tap Density Tester (Vankel, Cary, N.C.) or a SOTAX TapDensity Tester model TD1 (Horsham, Pa.). Tap density is a standardmeasure of the envelope mass density. The envelope mass density of anisotropic particle is defined as the mass of the particle divided by theminimum spherical envelope volume within which it can be enclosed.

Bulk Density.

Bulk density was estimated prior to tap density measurement by dividingthe weight of the powder by the volume of the powder, as estimated usingthe volumetric measuring device.

Emitted Geometric or Volume Diameter.

The volume median diameter (VMD) (Dv50) of the powder after it emittedfrom a dry powder inhaler, which may also be referred to as volumemedian geometric diameter (VMGD) and x50, was determined using a laserdiffraction technique via the Spraytec diffractometer (Malvern, Inc.,Westborough, Mass.). Powder was filled into size 3 capsules (V-Caps,Capsugel) and placed in a capsule based dry powder inhaler (RS01 Model 7High resistance, Plastiape, Italy), or DPI, which was joined via anairtight connection to the inhaler adapter of the Spraytec. A steadyairflow rate was drawn through the DPI typically at 60 L/min for a setduration, typically of 2 seconds controlled by a timer controlledsolenoid (TPK2000, Copley, Scientific, UK). The outlet aerosol thenpassed perpendicularly through the laser beam as an internal flow. Theresulting geometric particle size distribution of the aerosol wascalculated from the software based on the measured scatter pattern onthe photodetectors with samples typically taken at 1000 Hz for theduration of the inhalation. The Dv50, GSD, and FPF<5.0 μm measured werethen averaged over the duration of the inhalation.

Fine Particle Dose.

The fine particle dose is determined using the information obtained bythe ACI. The cumulative mass deposited on the filter, and stages 6, 5,4, 3, and 2 for a single dose of powder actuated into the ACI is equalto the fine particle dose less than 4.4 microns (FPD<4.4 μm).

Capsule Emitted Powder Mass.

A measure of the emission properties of the powders was determined byusing the information obtained from the ACI tests or emitted geometricdiameter by Spraytec. The filled capsule weight was recorded at thebeginning of the run and the final capsule weight was recorded after thecompletion of the run. The difference in weight represented the amountof powder emitted from the capsule (CEPM or capsule emitted powdermass). The CEPM was reported as a mass of powder or as a percent bydividing the amount of powder emitted from the capsule by the totalinitial particle mass in the capsule.

Example 1 Production and Characterization of Monovalent Cation DryPowders

Several powders of the invention were produced by spray drying ofhomogenous particles. The dry powders produced are shown in Table 1.

TABLE 1 Composition of monovalent cation dry powders. % % % SaltExcipient Drug load load load Form. Salt (w/w) Excipient (w/w) Drug(w/w) I Sodium 65.4 Leucine 30 fluticasone 4/0.58 chloride propionate/salmeterol xinafoate (FP/SX) II Sodium 10 Mannitol 85.42 FP/SX 4/0.58lactate III Potassium 60 Trehalose 30 budesonide 10 chloride IV Sodium40 Mannitol 10 ciprofloxacin 50 chloride V Potassium 5 Maltodextrin 45tobramycin 50 citrate VI Sodium 40.9 Leucine 59.1 N/A N/A chloride VIISodium 67.7 Leucine 30 FP/SX 2.0/0.29   chloride VIII Sodium 66.7Leucine 30 FP/SX 2.9/0.42   chloride IX N/A N/A Leucine 95.4 FP/SX4/0.58 X Sodium 65.4 Lactose 30 FP/SX 4/0.58 chloride XI N/A N/A Lactose95.4 FP/SX 4/0.58

The materials used to make the above powders and their sources are asfollows. Potassium chloride, potassium citrate, sodium chloride, sodiumlactate, L-leucine, lactose monohydrate, maltodextrin, mannitol,trehalose, budesonide, ciprofloxacin hydrochloride, fluticasonepropionate (FP), salmeterol xinafoate (SX) and tobramycin were obtainedfrom Sigma-Aldrich Co. (St. Louis, Mo.) or Spectrum Chemicals (Gardena,Calif.), except for sodium lactate (Chem Service, West Chester, Pa.),potassium chloride (Fisher Scientific, Pittsburgh, Pa.) and trehalose(Acros Organics, Morris Plane, N.J.). Ultrapure water was from a waterpurification system (Millipore Corp., Billerica, Mass.). Ethyl alcohol(200 Proof, ACS/USP Grade) was from Pharmco-Aaper (Shelbyville, Ky.).

Spray drying homogenous particles requires that the ingredients ofinterest be solubilized in solution or suspended in a uniform and stablesuspension. Most of the materials mentioned in the material section aresufficiently water-soluble to prepare suitable spray drying solutions.However, budesonide, flucticasone propionate and salmeterol xinafoateare practically insoluble in water. As a result of these lowsolubilities, formulation feedstock development work was necessary toprepare solutions or suspensions that could be spray dried. Budesonide,flucticasone propionate and salmeterol xinafoate are slightly soluble inethanol, so these were fully solubilized in 99% ethanol prior to mixingwith other components dissolved in water to obtain a 2-10 g/L solidsconcentration in 60% ethanol solution.

For the spray drying process, the salts, excipients and other drugs weredissolved or suspended in a solvent (e.g., water). The solidconcentrations (w/v) were chosen dependent on the solubility of thedifferent components (see Table 2). The ratios used for formulationswere based on the molecular weight of the anhydrous salts (see Table 3).

TABLE 2 Salt solubilities Salt Water solubility at 20-30° C., 1 barPotassium chloride 1 g/2.8 mL¹ Potassium citrate Monohydrate, 1 g/0.65mL¹ Sodium ascorbate 62 g/100 mL¹ Sodium bicarbonate Soluble in 10parts¹ Sodium carbonate Soluble in 3.5 parts¹ Sodium chloride 1 g/2.8mL¹ Sodium citrate Dihydrate, soluble in 1.3 parts¹ Sodium lactateCommercially available as 70-80% in water¹ Dibasic sodium phosphateSoluble in ~8 parts¹ Sodium propionate 1 g/~1 mL¹ Sodium sulfate Solublein 3.6 parts¹ ¹O'Neil, Maryadele J. The Merck Index: an Encyclopedia ofChemicals, Drugs, and Biologicals. 14th ed. Whitehouse Station, N.J.:Merck, 2006.

TABLE 3 Weight Percent K⁺ and Na⁺ in Salt Molecules Weight % ofMolecular cation in Salt Formula MW (g/mol) molecule Potassium chlorideKCl 74.55 52.45 Potassium citrate C₆H₅K₃O₇ 306.39 38.28 Sodium ascorbateC₆H₇NaO₆ 198.11 20.23 Sodium bicarbonate CHNaO₃ 84.01 47.71 Sodiumcarbonate CNa₂O₃ 105.99 43.38 Sodium chloride NaCl 58.44 39.34 Sodiumcitrate C₆H₅Na₃O₇ 258.07 26.73 Sodium lactate C₃H₅NaO₃ 112.06 20.52Dibasic sodium phosphate HNa₂O₄P 141.96 28.23 Sodium propionate C₃H₅NaO₂96.06 41.72 Sodium sulfate Na₂O₄S 142.04 32.37

Dry powders were prepared by spray drying on a Büchi B-290 Mini SprayDryer (BÜCHI Labortechnik AG, Flawil, Switzerland) with powdercollection from a High Performance cyclone. The system used the BüchiB-296 dehumidifier to ensure stable temperature and humidity of the airused to spray dry. Furthermore, when the relative humidity in the roomexceeded 30% RH, an external LG dehumidifier (model 49007903, LGElectronics, Englewood Cliffs, N.J.) was run constantly. Atomization ofthe liquid feed utilized a Büchi two-fluid nozzle with a 1.5 mmdiameter. Inlet temperature of the process gas can range from 100° C. to220° C. and outlet temperature from 80° C. to 120° C. with a liquidfeedstock flowrate of 3 mL/min to 10 mL/min. The two-fluid atomizing gasranges from 25 mm to 45 mm (300 LPH to 530 LPH) and the aspirator ratefrom 70% to 100%. The feedstock was prepared as a batch by dissolvingthe specific salt in ultrapure water, then the excipient, and finallythe drug component. For Formulations I-III and VII-IX where budesonide,FP and SX are practically insoluble in water, but slightly soluble inethanol, the drug components were fully dissolved in ethanol and mixedslowly with the aqueous solution (salt and excipient previouslydissolved in water) to avoid precipitation. The solution was keptagitated throughout the process until the materials were completelydissolved in the water or ethanol solvent system at room temperature.

Formulation I dry powders were produced by spray drying on the BüchiB-290 Mini Spray Dryer (BÜCHI Labortechnik AG, Flawil, Switzerland) withpowder collection in a 60 mL glass vessel from a High Performancecyclone. The system used the Büchi B-296 dehumidifier and an external LGdehumidifier (model 49007903, LG Electronics, Englewood Cliffs, N.J.)was run constantly. Atomization of the liquid feed utilized a Büchitwo-fluid nozzle with a 1.5 mm diameter. The two-fluid atomizing gas wasset at 40 mm and the aspirator rate to 90%. Room air was used as thedrying gas. Inlet temperature of the process gas was 180° C. and outlettemperature from 86° C. to 87° C. with a liquid feedstock flow rate of 8mL/min to 9 mL/min. The solids concentration was 10 g/L in 60% ethanol.

Formulation II was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from83° C. to 85° C. with a liquid feedstock flow rate of 9 mL/min. Thesolids concentration was 5 g/L in 60% ethanol.

Formulation III was produced using the same equipment and settings.Inlet temperature of the process gas was 180° C. and outlet temperaturefrom 92° C. to 94° C. with a liquid feedstock flow rate of 6 mL/min to 7mL/min. The solids concentration was 5 g/L in 60% ethanol.

Formulation IV was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from75° C. to 81° C. with a liquid feedstock flow rate of 6 mL/min. Thesolids concentration was 10 g/L in ultrapure water.

Formulation V was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from81° C. to 86° C. with a liquid feedstock flow rate of 6 mL/min to 7mL/min. The solids concentration was 5 g/L in ultrapure water.

Formulation VI was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from61° C. to 87° C. with a liquid feedstock flow rate of 6 mL/min. Thesolids concentration was 5 g/L in 60% ethanol.

Formulation VII was produced using the same equipment and settings.Inlet temperature of the process gas was 180° C. and outlet temperaturefrom 88° C. to 89° C. with a liquid feedstock flow rate of 9 mL/min to10 mL/min. The solids concentration was 10 g/L in 60% ethanol.

Formulation VIII was produced using the same equipment and settings.Inlet temperature of the process gas was 180° C. and outlet temperaturefrom 84° C. to 85° C. with a liquid feedstock flow rate of 9 mL/min to10 mL/min. The solids concentration was 10 g/L in 60% ethanol.

Formulation IX was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from76° C. to 87° C. with a liquid feedstock flow rate of 9 mL/min to 10mL/min. The solids concentration was 5 g/L in 60% ethanol.

Formulation X was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from86° C. to 87° C. with a liquid feedstock flow rate of 9 mL/min to 10mL/min. The solids concentration was 5 g/L in 60% ethanol.

Formulation XI was produced using the same equipment and settings. Inlettemperature of the process gas was 180° C. and outlet temperature from87° C. to 88° C. with a liquid feedstock flow rate of 9 mL/min to 10mL/min. The solids concentration was 5 g/L in 60% ethanol.

Formulations I, II and VII-XI comprise FP, SX and excipients. The drugloading for FP ranged from 2.0 to 4.0 wt %, while that of SX ranged from0.29 to 0.58 wt %. The higher drug loads are comparable to the amount ofdrug contained within a single dosage unit of a commercial formulationof FP and SX. The lower drug loads take into account depositionefficiency of the commercial formulation, as well as anticipated aerosolproperties of the formulations produced here, to target a nominal drugmass that results in the desired drug dose.

The spray drying process yield was obtained by calculating the ratio ofthe weight of dry powder collected after the spray drying process wascompleted divided by the weight of the starting solid components placedinto the spray drying liquid feed.

The FPF_TD (<5.6 microns) and FPF_TD (<3.4 microns) were measured bycharacterizing the powders with a two stage ACI using stages 0, 2 and F.Powder formulations were filled into size 3 HPMC capsules by hand withthe fill weight measured gravimetrically using an analytical balance.Fill weights of 20 mg were filled for Formulations I-III and VI-XI, 40mg for Formulation VII and 50 mg for Formulations IV and V. An RS-01 DPIwas used to disperse the powder into the cascade impactor. One capsulewas used for each measurement, with two actuations of 2 L of air at 60LPM drawn through the dry powder inhaler (DPI). The flow rate andinhaled volume were set using a timer controlled solenoid valve withflow control valve. Three replicate ACI measurements were performed foreach formulation. The impactor stage plates were inverted andpre-weighed 81 mm glass fiber filters were placed on them. After theinhalation maneuver, the impactor was disassembled and the glass fiberfilters were weighed. Powder that is collected on stage two is composedof respirable dry particles that have an aerodynamic diameter of lessthan 5.6 microns and greater than 3.4 microns. The fraction of powderpassing stage two and depositing on a collection filter on stage F isthus composed of respirable dry particles having an aerodynamic diameterof less than 3.4 microns. The results of the size characterization ofthe powders are shown in Table 4 below.

TABLE 4 Size characteristics of monovalent cation dry powders. SprayDrying FPF_TD FPF_TD Yield <3.4 μm <5.6 μm Formulation (%) (%) (%) INaCl:Leu:FP/SX 52.1% 59.1% 72.3% II NaLac:Mann:FP/SX 44.7% 2.6% 12.5%III KCl:Tre:Budes 44.9% 42.2% 48.7% IV NaCl:Mann:Cipro 81.4% 27.1% 48.3%V KCit:Malt:Tobra 69.2% 35.9% 51.8% VI NaCl:Leu 40.0% 66.9% 82.3% VIINaCl:Leu:FP/SX 54.7% 59.1% 76.4% VIII NaCl:Leu:FP/SX 58.7% 53.1% 74.9%IX Leu:FP/SX 43.5% 26.1% 40.0% X NaCl:Lact:FP/SX 50.0% 24.6% 44.9% XILact:FP/SX 44.7% 46.0% 70.2%

The powders produced were further characterized with regard to densityand dispersibility ratio.

Bulk and tapped densities were determined using a SOTAX Tap DensityTester model TD1 (Horsham, Pa.). For any given run, a sample wasintroduced to a tared 0.3 cc section of a disposable serologicalpolystyrene micropipette (Grenier Bio-One, Monroe, N.C.) using a funnelmade with weighing paper (VWR International, West Chester, Pa.) and thepipette section was plugged with polyethylene caps (Kimble Chase,Vineland, N.J.) to hold the powder. The powder mass and initial volume(V₀) were recorded and the pipette was attached to the anvil and runaccording to the USP I method. For the first pass, the pipette wastapped using Tap Count 1 (500 taps) and the resulting volume V_(a) wasrecorded. For the second pass, Tap Count 2 was used (750 taps) resultingin the new volume V_(b1). If V_(b1)>98% of V_(a), the test was complete,otherwise Tap Count 3 was used (1250 taps) iteratively until V_(bn)>98%of V_(bn-1). Bulk density was estimated prior to tap density measurementby dividing the weight of the powder by the volume of the powder, asestimated using the volumetric measuring device. Calculations were madeto determine the powder bulk density (d_(B)), tap density (d_(T)), andHausner Ratio (H), which is the tap density divided by the bulk density.

Volume median diameter was determined using a HELOS laser diffractometerand a RODOS dry powder disperser (Sympatec, Inc., Princeton, N.J.). Amicrospatula of material (approximately 5 milligrams) was introducedinto the RODOS funnel, where a shear force is applied to a sample ofparticles as controlled by the regulator pressure of the incomingcompressed dry air. The pressure settings were varied to use differentamounts of energy to disperse the powder. The regulator pressure was setat 0.2 bar, 0.5 bar, 1.0 bar, 2.0 bar and 4.0 bar, with maximum orificering pressure at each pressure. The dispersed particles traveled througha laser beam where the resulting diffracted light pattern produced iscollected, using an R1 or R3 lens, by a series of detectors. Theensemble diffraction pattern is then translated into a volume-basedparticle size distribution using the Fraunhofer diffraction model, onthe basis that smaller particles diffract light at larger angles. 1bar/4 bar, 0.5 bar/4 bar, 0.2 bar/4 bar ratios were obtained by dividingaverage volume median diameter values obtained at each of 0.2 bar, 0.5bar and 1.0 bar by the volume median diameter value obtained at 4.0 bar.

Results for the density tests for the formulations are shown in Table 5.The tap densities for Formulations I-X were relatively high (e.g., >0.4g/cc). The bulk densities were such that the Hausner ratio was alsorather high for all formulations, particularly Formulations II and IX.All of the powders tested possessed Hausner Ratios that have beendescribed in the art as being characteristic of powders with extremelypoor flow properties (See, e.g., USP <1174>). USP <1174> notes that drypowders with a Hausner ratio greater than 1.35 are poor flowing powders.Flow properties and dispersibility are both negatively affected byparticle agglomeration or aggregation. It is therefore unexpected thatpowders with Hausner Ratios of 1.9 to 3.3 would be highly dispersibleand possess good aerosolization properties

TABLE 5 Characteristics of monovalent cation dry powders. Density BulkTap HELOS/RODOS VMGD Density Density Hausner 1/4 0.5/4 0.2/4 at 1 barFormulation (g/cc) (g/cc) Ratio bar bar bar (μm) I 0.23 ± 0.01 0.48 ±0.11 2.09 1.19 1.36 1.42 1.58 NaCl:Leu: FP/SX II 0.12 ± 0.02 0.39 ± 0.113.25 1.10 1.62 2.12 11.00 NaLac:Mann: FP/SX III 0.29 ± 0.03 0.59 ± 0.002.03 1.18 1.39 1.83 1.27 KCl:Tre: Budes IV 0.32 ± 0.13 0.60 ± 0.02 1.880.92 1.00 1.21 2.00 NaCl:Mann: Cipro V 0.29 ± 0.01 0.56 ± 0.00 1.93 1.101.16 1.40 1.55 KCit:Malt: Tobra VI 0.21 ± 0.11 0.41 ± 0.02 1.94 1.091.11 1.26 1.89 NaCl:Leu VII 0.24 ± 0.01 0.49 ± 0.00 2.04 1.11 1.16 1.251.76 NaCl:Leu:FP/SX VIII 0.24 ± 0.03 0.47 ± 0.03 1.96 1.13 1.30 1.411.56 NaCl:Leu:FP/SX IX 0.22 ± 0.02 0.45 ± 0.02 2.07 1.25 1.40 2.46 1.88Leu:FP/SX X 0.37 ± 0.01 0.76 ± 0.08 2.05 1.07 1.32 1.93 1.44NaCl:Lact:FP/S XI 0.10 ± 0.00 0.19 ± 0.00 1.86 1.05 1.17 1.36 1.89Lact:FP/SX

Table 5 further shows that Formulations I-XI have a HELOS/RODOSdispersibility ratio at 1/4 bar between 0.92 and 1.25, at 0.5/4 barbetween 1.00 and 1.62, and at 0.2/4 bar between 1.21 and2.46. Valuesthat are close to 1.0, as these values are, are considered indicative ofpowders that are highly dispersible. In particular, Formulation I, IV,V-VIII and XI displayed highly dispersible behavior, as all haddispersive pressure ratios less than about 1.4

Table 5 also shows the VMGD at 1 bar for Formulations I through XI. TheVMGD for all the formulations except for Formulation II is between about1.2 microns and about 2.0 microns.

Example 2 Dispersibility of Monovalent Cation Powders

This example demonstrates the dispersibility of dry powder formulationswhen delivered from a dry powder inhaler over a range of inhalation flowrate and volumes.

The dispersibility of various powder formulations was investigated bymeasuring the geometric particle size distribution and the percentage ofpowder emitted from capsules when inhaling on a dry powder inhaler withflow rates representative of patient use. The particle size distributionand weight change of the filled capsules were measured for multiplepowder formulations as a function of flow rate and inhaled volume in apassive dry powder inhaler.

Powder formulations were filled into size 3 HPMC capsules (CapsugelV-Caps) by hand with the fill weight measured gravimetrically using ananalytical balance (Mettler Toledo XS205). Fill weights of 20 mg werefilled for Formulations I and III. A capsule-based passive dry powderinhaler (RS-01 Model 7, High Resistance, Plastiape S.p.A.) was usedwhich had specific resistance of 0.036 kPa^(1/2)LPM⁻¹. Flow rate andinhaled volume were set using a timer controlled solenoid valve and flowcontrol valve with an inline mass flow meter (TSI model 3063). Capsuleswere placed in the dry powder inhaler, punctured and the inhaler sealedinside a cylinder, exposing the air jet exiting from the DPI to thelaser diffraction particle sizer (Spraytec, Malvern) in its open benchconfiguration. The steady air flow rate through the system was initiatedusing the solenoid valve and the particle size distribution was measuredvia the Spraytec at lkHz for the duration of the single inhalationmaneuver with a minimum of 2 seconds. Particle size distributionparameters calculated included the volume median diameter (Dv50) and thegeometric standard deviation (GSD). At the completion of the inhalationduration, the dry powder inhaler was opened, the capsule removed andre-weighed to calculate the mass of powder that had been emitted fromthe capsule during the inhalation duration. Two inhalation conditionswere used for each powder including 60 LPM and 2 L for the highinhalation energy condition and 30LPM and 1 L for the low inhalationenergy condition. At each inhalation condition, 5 replicate capsuleswere measured and the results of Dv50, GSD and capsule emitted powdermass (CEPM) were averaged.

In order to relate the dispersion of powder at different flow rates,volumes, and from inhalers of different resistances, the energy requiredto perform the inhalation maneuver was calculated. Inhalation energy wascalculated as E=R²Q²V where E is the inhalation energy in Joules, R isthe inhaler resistance in kPa^(1/2)/LPM, Q is the steady flow rate inL/min and V is the inhaled air volume in L. In the example describedhere, the inhalation energy for the case of 60 LPM and 2 L was 9.2Joules, while for the other case of 30 LPM and 1 L, the inhalationenergy was 1.2 Joules.

Table 6 shows the dose emitted from a capsule (CEPM), and the particlesize distribution parameters of the powder emitted (Dv50 and GSD) forFormulations I and III at a capsule fill weight of 20 mg using the highresistance RS-01 dry powder inhaler. For each powder, a 2 L inhalationwas used at the high flow rate condition of 60 LPM and a 1 L inhalationfor the 30 LPM condition. For Formulation I, the CEPM decreased modestlyfrom 62% to 44% while the volume median diameter increased only slightlyfrom 1.60 to 1.77 μm with a drop of inhalation energy from 9.2 to 1.2Joules. For Formulation III, while the CEPM did decrease from 90 to 55%,more than 50% of the filled powder weight was emptied from the capsuleat the low energy condition. The Dv50 of the emitted powder was lessthan 5 micrometers for both inhalation conditions.

TABLE 6 Aerosol properties of monovalent powders. Flow Rate: (LPM) 60 30Formulation I Dv(50) (μm): 1.60 ± 0.06 1.77 ± 0.20 NaCl:Leu: GSD (μm):2.94 ± 0.46 4.27 ± 0.53 FP/SX CEPM (%): 62% 44% Formulation III Dv(50)(μm): 1.63 ± 0.05 3.43 ± 0.74 KCl:Tre: GSD (μm): 4.87 ± 0.83 7.09 ± 1.38Budes CEPM (%): 90% 55%

Table 7 shows the dose emitted from a capsule (CEPM) and the particlesize distribution parameters of the powder emitted Dv(50) forFormulations VI through XI at the indicated capsule fill weight usingthe high resistance RS-01 dry powder inhaler across several flow rates.In this example, the inhaler resistance was 0.036 kPa^(1/2)/LPM and theinhalation energy for 60 LPM and 2 L was 9.2 Joules, for 30 LPM and 1 Lwas 1.2 Joules, for 20 LPM and 1 L was 0.52 Joules and for 15 LPM and 1L was 0.29 Joules.

TABLE 7 Aerosol properties of monovalent cation-based dry powderformulations of FP/SX. Flow Rate: (LPM) 60 30 20 15 Formulation VIDv(50) 2.4 N/A N/A N/A NaCl:Leu (μm): CEPM N/A N/A N/A N/A FormulationVII-1 Dv(50) 1.37 ± 0.15 2.29 ± 0.06 3.53 ± 0.18 5.43 ± 0.42NaCl:Leu:FP/SX (μm): (40 mg capsule fill) CEPM (%): 99.1 ± 0.1  69.5 ±26.8 54.9 ± 26.9 36.1 ± 16.5 Formulation VII-2 Dv(50) N/A N/A N/A 5.33 ±0.13 NaCl:Leu:FP/SX (μm): CEPM (%): N/A N/A N/A 90.7 ± 2.8 FormulationVIII Dv(50) 1.62 ± 0.17 2.48 ± 0.67 3.65 ± 0.08 5.42 ± 0.16NaCl:Leu:FP/SX (μm): CEPM (%): 97.9 ± 0.4  94.1 ± 03.3 87.1 ± 16.1 92.5± 4.4  Formulation IX Dv(50) 2.79 ± 0.25 3.81 ± 0.12 6.24 ± 0.16 8.23 ±0.51 Leu:FP/SX (μm): CEPM (%): 99.1 ± 0.1  98.2 ± 0.3  97.1 ± 0.9  80.7± 11.4 Formulation X Dv(50) 1.96 ± 0.22 31.11 ± 6.96  87.03 ± 22.4396.81 ± 11.81 NaCl:Lact:FP/SX (μm): CEPM (%): 83.5 ± 14.7 40.6 ± 22.344.4 ± 19.9 43.5 ± 18.4 Formulation XI Dv(50) 2.47 ± 0.16 7.95 ± 0.8839.61 ± 11.08 61.16 ± 4.71  Lact:FP/SX (μm): CEPM (%): 91.9 ± 2.8 49.9 ±19.6 47.8 ± 21.8 32.5 ± 17.5

All powder formulations at 60 LPM and 2 L were well dispersed from thedry powder inhaler with all listed formulations having greater than 80%of the filled powder mass emptying from the capsules and medianvolumetric diameters of less than 5 micrometers. At the 30 LPM and 1 Lcondition corresponding to 1.2 Joules, formulations VIII and IXmaintained a CEPM greater than 80% and volume median diameter of lessthan 5 micrometers, with only modest increases in diameter measured foreither formulation. At the lowest flow rate condition of 15 LPM and 1 Lcorresponding to 0.3 Joules of inhalation energy, Formulations VII-2,VIII, and IX all showed greater than 80% CEPM and volume mediandiameters below 10 micrometers which is very good dispersibility at sucha low applied energy condition.

Example 3 Aerodynamic Particle Size of Monovalent Cation Powders

This example demonstrates that the aerodynamic size distribution of drypowder formulations comprised in part of monovalent cationic salts, whendelivered from a dry powder inhaler, is in a range appropriate fordeposition in the respiratory tract.

The aerodynamic particle size distributions of five powder formulationswere measured by characterizing the powders with an eight stage ACI.Powder formulations were filled into size 3 HPMC capsules (V-Caps,Capsugel) by hand with the fill weight measured gravimetrically using ananalytical balance (Mettler Toledo XS205). Fill weights of 20 mg werefilled for Formulations I, II, and III, and a fill weights of 50 mg werefilled for Formulations IV and V. A reloadable, capsule-based passivedry powder inhaler (RS-01 Model 7, High Resistance, Plastiape, Osnago,Italy) was used to disperse the powder into the cascade impactor. Onecapsule was used for each measurement, with two actuations of 2 L of airat 60 LPM drawn through the dry powder inhaler (DPI). The flow rate andinhaled volume were set using a timer controlled solenoid valve withflow control valve (TPK2000, Copley Scientific). Three replicate ACImeasurements were performed for each formulation. The impactor stageplates were inverted and pre-weighed 81 mm glass fiber filters(1820-6537, Whatman) were placed on them. After the inhalation maneuver,the impactor was disassembled and the glass fiber filters were weighedto determine the mass of powder deposited on each stage and on the finalfilter. The size distribution of the emitted powder was averaged acrossthe replicates and the average mass of powder delivered to each of thestages (−1, −0, 1, 2, 3, 4, 5, 6, and F) are shown for each formulationin FIGS. 1A to 1E with error bars giving standard deviation of the 3replicates. The mass median aerodynamic diameter (MMAD), geometricstandard deviation (GSD), and fine particle dose (FPD<4.4 μm) of theemitted powder were calculated and averaged across the replicates andare tabulated in Table 8.

TABLE 8 Aerodynamic particle size of monovalent cation dry powderformulations. aPSD (ACI-8) MMAD GSD FPD < 4.4 μm Formulation (μm) (μm)(mg) I 3.01 ± 0.16 1.81 ± 0.04 11.2 ± 0.8 NaCl:Leu:FP/SX II 8.56 ± 0.401.62 ± 0.06  0.73 ± 0.04 NaLac:Mann:FP/SX III 2.18 ± 0.10 1.71 ± 0.038.6 + 0.2 KCl:Tre:Budes IV 3.88 ± 0.10 1.75 ± 0.02 15.4 ± 0.7NaCl:Mann:Cipro V 2.91 ± 0.11 1.83 ± 0.00 21.1 + 1.4 KCit:Malt:Tobra

All five formulations were found to have repeatable size distributionsas illustrated by the low standard deviations for all the stages andcalculated values. All five formulations had respirable sizedistributions with Formulations I, III, IV and V having MMADs less than5 micrometers and Formulation II having an MMAD less than 10micrometers.

With a maximum GSD of 1.83 for the five formulations, the polydispersityof the size distributions was relatively small compared to typical drypowder formulations for inhalation. The fine particle dose shown inTable 8 for the five powder formulations demonstrated that a significantmass of the powder dose was contained in small diameter particles thatwould be expected to deposit in the lung.

Example 4 Production and Optimization of Monovalent Cation Dry Powders

Several monovalent cation powders comprised of sodium sulfate andmannitol or maltodextrin were produced by spray drying of homogeneousparticles. The powders produced are shown below in Table 9.

TABLE 9 Composition of monovalent cation dry powders. % % Salt Excipientload load Formulation Salt (w/w) Excipient (w/w) XII Sodium 90 Mannitol10 sulfate XIII Sodium 50 Mannitol 50 sulfate XIV Sodium 10 Mannitol 90sulfate XV Sodium 90 Maltodextrin 10 sulfate XVI Sodium 50 Maltodextrin50 sulfate XVII Sodium 10 Maltodextrin 90 sulfate

The materials to make the above powders and their sources are asfollows: sodium sulfate, mannitol and maltodextrin were purchased fromSpectrum Chemicals (Gardena, Calif.). Ultrapure water was from a waterpurification system (Millipore Corp., Billerica, Mass.).

Formulation XII-XVII dry powders were prepared by spray drying on aBüchi B-290 Mini Spray Dryer (BÜCHI Labortechnik AG, Flawil,Switzerland) with powder collection from a High Performance cyclone. Thesystem used the Büchi B-296 dehumidifier to ensure stable temperatureand humidity of the air used to spray dry. Atomization of the liquidfeed utilized a Büchi two-fluid nozzle with a 1.5 mm diameter. Inlettemperature of the process gas was 100° C. and outlet temperature rangedfrom 51° C. to 58° C. with a liquid feedstock flowrate of 2.6 mL/min.The two-fluid atomizing gas was set to 40 mm (473 LPH) and the aspiratorrate to 80% (33 m³/h). Room air was used as the drying gas. Thefeedstock was prepared as a batch by dissolving the specific salt inultrapure water, then the excipient, and finally the drug component. Thesolution was kept agitated throughout the process until the materialswere completely dissolved in the water solution at room temperature. Thesolids concentration was 10 g/L in 60% ultrapure water.

As shown in Table 10, all the powders had acceptable yields (dry powderoutput collected divided by the total solids added to the solution) fromthe spray drying process. The powders produced were then characterizedwith regard to size (FPF_TD<3.4 μm and <5.6 μm) using a two-stage ACI asdescribed in Example 1. The large percentage of particles with a FPF_TDless than 5.6 μm and less than 3.4 gm indicated that the powderparticles were respirable and of the appropriate size for deposition inthe lung.

TABLE 10 Size characteristics of monovalent cation dry powders. SprayDrying FPF_TD FPF_TD Yield <3.4 μm <5.6 μm Formulation (%) (%) (%) XII81 27 49 XIII 79 26 49 XIV 77 32 54 XV 83 39 59 XVI 82 33 51 XVII 75 3048

Bulk and tapped densities of the powders were determined using a TD1 asdescribed in Example 1. Results for the density tests for formulationsXII-XVII are shown in Table 11.

TABLE 11 Characterization of monovalent cation dry powders. DensityHELOS/RODOS VMGD Bulk Density Tap Density Hausner 1/4 0.5/4 0.2/4 at 1bar Formulation (g/cc) (g/cc) Ratio bar bar bar (μm) XII N/A N/A N/A1.18 0.68 0.94 5.34 XIII 0.42 ± 0.03 0.88 ± 0.00 2.11 1.04 1.12 1.311.80 XIV 0.38 ± 0.03 0.83 ± 0.05 2.19 1.04 1.06 1.17 1.97 XV 0.34 ± 0.060.79 ± 0.28 2.31 1.20 1.07 1.13 2.34 XVI 0.41 ± 0.02 0.88 ± 0.01 2.150.97 1.01 1.05 1.76 XVII 0.29 ± 0.03 0.57 ± 0.06 1.93 1.01 0.98 1.202.12

The tap densities of Formulations XIII-XVII were high (e.g., >than 0.4g/cc) and their Hausner ratios were well above 1.35, a ratio typicallyindicative of powders with poor flowability and dispersibility. However,measurement of the dispersibility properties of the powders indicatedthat the formulations were surprisingly dispersible, in spite of havinghigh Hausner ratios.

Table 11 also shows the VMGD for Formulations XII through XVII at 1 bar.The VMGD at 1 bar for Formulations XIII through XVII is between about1.7 microns to about 2.4 microns.

The dispersibility of the dry powder formulations was assessed bymeasuring geometric particle size distribution Dv(50) and percentage ofpowder emitted from capsules (CEPM) at different flow ratesrepresentative of patient use. The Dv(50) and CEPM of FormulationsXII-XVII were measured as described in Example 2, and the results areshown in Table 12.

TABLE 12 Aerosol properties of monovalent cation dry powders. Flow Rate:(LPM) Formulation 60 30 20 15 XII Dv(50) (μm): 2.29 ± 0.02 2.33 ± 0.032.58 ± 0.08 3.10 ± 0.10 CEPM (%): 91.2 ± 1.7 73.2 ± 12.5 47.2 ± 21.039.5 ± 15.6 XIII Dv(50) (μm): 2.19 ± 0.05 2.34 ± 0.03 2.70 ± 0.05 3.35 ±0.04 CEPM (%): 98.4 ± 0.8 97.2 ± 0.5 93.7 ± 2.6 92.8 ± 4.0 XIV Dv(50)(μm): 2.16 ± 0.07 2.30 ± 0.02 2.70 ± 0.05 3.26 ± 0.09 CEPM (%): 94.6 ±0.8 88.8 ± 2.2 78.2 ± 10.9 78.8 ± 4.3 XV Dv(50) (μm): 1.98 ± 0.01 2.03 ±0.02 2.17 ± 0.04 2.70 ± 0.11 CEPM (%): 92.9 ± 2.0 76.5 ± 5.9 71.0 ± 9.954.5 ± 24.8 XVI Dv(50) (μm): 1.88 ± 0.02 1.93 ± 0.01 2.34 ± 0.06 3.10 ±0.17 CEPM (%): 85.9 ± 2.9 64.3 ± 2.9 53.4 ± 13.5 64.0 ± 4.4 XVII Dv(50)(μm): 2.39 ± 0.03 2.58 ± 0.08 3.37 ± 0.15 5.16 ± 1.49 CEPM (%): 90.2 ±3.3 36.5 ± 13.0 31.7 ± 21.8 30.1 ± 15.6

All powder formulations at 60 LPM and 2 L were well dispersed from thedry powder inhaler with all listed formulations having greater than 80%of the filled powder mass emptying from the capsules and medianvolumetric diameters of less than 5 micrometers. At the 30 LPM and 1 Lcondition corresponding to 1.2 Joules, all formulations still had volumemedian diameters of less than 5 micrometers and all except formulationXVII had greater than 60% of the powder mass emitted from the capsule.At the lowest flow rate condition of 15 LPM and 1 L corresponding to 0.3Joules of inhalation energy, all the formulations showed littleagglomeration with volume median diameters of less than 5 micrometersand formulations XIII, XIV and XVI having greater than 60% of the powdermass emitted from the capsule, a very good dispersibility a such a lowapplied energy condition.

Example 5 Sodium Salt-Containing Dry Powders, Optionally Combined withActive Pharmaceutical Agents

A. Powder Preparation.

Feedstock solutions were prepared in order to manufacture dry powderscomprised of dry particles containing a sodium salt, optionally anon-salt excipient, and at least one pharmaceutical active agent. Table13 lists the components of the feedstock formulations used inpreparation of the dry powders comprised of dry particles. Weightpercentages are given on a dry basis.

TABLE 13 Feedstock compositions of sodium-salt with otherpharmaceutically active agents % % % Salt Excipient Drug load load loadFormulation Salt (w/w) Excipient (w/w) Drug (w/w) XVIII Sodium 40.9Leucine 59.1 N/A  0 chloride XIX Sodium 34.5 Leucine 50.0 fluticasone13.5/2.0 Chloride propionate/ salmeterol xinafoate (FP/SX) XX Sodium65.42 Leucine 34.47 Tiotropium  0.113 Chloride Bromide (TioB) XXI Sodium53 Leucine 27 Levofloxacin 20 Chloride (Levo) XXII Sodium 85.31 Leucine10.0 FP/SX/TioB 4.0/0.58/ Chloride 0.113 XXIII Sodium 65.42 Leucine29.89 FP/SX/TioB 4.0/0.58/ Chloride 0.113 XXIV Sodium 50.0 Mannitol 40.0Insulin 10.0 sulfate XXV Sodium 50.0 Mannitol 47.5 Immunoglobulin  2.5sulfate G (IgG) XXVI Sodium 45.42 Leucine 50.0 FP/SX 4.0/0.58 citrateXXVII Sodium 45.42 Leucine 50.0 FP/SX 4.0/0.58 sulfate XXVIII Sodium55.0 Mannitol 40.0 Insulin  5.0 sulfate XXIX Potassium 50.0 Mannitol50.0 N/A N/A chloride XXX Potassium 10.0 Mannitol 90.0 N/A N/A chlorideXXXI Potassium 10.0 Mannitol 90.0 N/A N/A citrate XXXII Sodium 10.0Leucine/ 50.0/ TioB  0.113 lactate Maltodextrin 39.9 XXXIII Sodium 65.4Leucine 30.0 FP/SX 4.0/0.58 chloride N/A = not applicable

The feedstock solutions were made according to the parameters in Table14.

TABLE 14 Formulation Conditions Formulation: XVIII XIX XX XXI XXII Totalsolids (g) 10 7.5 3 5 10 Total volume water (L) 2 2.25 0.3 0.5 0.4 Totalsolids 5 3.3 10 10 10 concentration (g/L) Amount of NaCl in 1 L 2.051.15 6.542 5.3 8.531 (g) Amount leucine in 1 L 2.96 1.67 3.447 2.7 1.0(g) Amount FP in 1 L (g) 0 0.45 0 2.0 0.4 Amount SX in 1 L (g) 0 0.07 00 0.058 Amount TioB in 1 L (g) 0 0 0.0113 0 0.0113 Formulation: XXIIIXXIV XXV XXVI XXVII Total solids (g) 4 5 5 2 2 Total volume water (L)0.4 0.5 0.5 1 1 Total solids 10 10 10 2 2 concentration (g/L) Amount ofNaCl in 1 L 6.542 0 0 0 0 (g) Amount of NaSulf in 1 L 0 5.0 5.0 0 4.542(g) Amount of NaCit in 1 L 0 0 0 4.542 0 (g) Amount leucine in 1 L 2.9890 0 5.0 5.0 (g) Amount mannitol in 1 L 0 5.0 5.0 0 0 (g) Amount FP in 1L (g) 0.4 0 0 0.4 0.4 Amount SX in 1 L (g) 0.058 0 0 0.58 0.58 AmountTioB in 1 L (g) 0.0113 0 0 0 0 Amount Insulin in 1 L 0 1 0 0 0 (g)Amount IgG in 1 L (g) 0 0 0.25 0 0 Formulation: XXVIII XXIX XXX XXXIXXXII Total solids (g) 10 3 3 3 3 Total volume water (L) 0.667 0.3 0.30.3 0.3 Total solids 15 10 10 10 10 concentration (g/L) Amount of NaClin 1 L 0 0 0 0 0 (g) Amount of NaSulf in 1 L 5.5 0 0 0 0 (g) Amount ofNaLact in 1 L 0 0 0 0 1.0 (g) Amount of KCl in 1 L 0 5.0 1.0 0 0 (g)Amount of KCit in 1 L 0 0 0 1.0 0 (g) Amount leucine in 1 L 0 0 0 0 5.0(g) Amount mannitol in 1 L 4.0 5.0 9.0 9.0 0 (g) Amount maltodextrin in0 0 0 0 3.897 1 L (g) Amount TioB in 1 L (g) 0 0 0 0 0.113 AmountInsulin in 1 L 0.5 0 0 0 0 (g) For all formulations, the liquidfeedstock was batch mixed

The formulation conditions for Formulation XXXIII were: Total solidswere 3 grams (g), total volume was 0.3 liters, total solidsconcentration was 10 grams per liter, amount of NaCl, leucine, FP, andSX in one liter was 6.542 g, 3.0 g, 0.4 g, and 0.058 g, respectively.

Formulation XVIII through XXXIII dry powders were produced by spraydrying on the Büchi B-290 Mini Spray Dryer (BÜCHI Labortechnik AG,Flawil, Switzerland) with powder collection from a High Performancecyclone in a 60 mL glass vessel. The system used the Büchi B-296dehumidifier and an external LG dehumidifier (model 49007903, LGElectronics, Englewood Cliffs, N.J.) was run constantly, except forFormulation XXXII. Atomization of the liquid feed utilized a Büchitwo-fluid nozzle with a 1.5 mm diameter except for Formulation XXXII,which used a two-fluid nozzle with a 1.4 mm diameter. The two-fluidatomizing gas was set at 40 mm (667 LPH). The aspirator rate was set to90% (35 m³/h) for Formulations XVIII, XIX and XXI; to 80% (32 m³/h) forFormulations XX, XXIV, XXV, VVIIII, XXIX, XXX, XXXI and XXXIII; 70% forFormulations XXII, XXIII, XXVI, XXVII. Formulation XXXII had anaspirator rate of 100%, but nitrogen flow limited rate to approximately31 kg/h or 26 m³/h. Air was used as the drying gas and the atomizationgas, except for Formulation XXXII, where nitrogen was used. Table 15below includes details about the spray drying conditions.

Formulation XXXIII was essentially the same formulation as FormulationI. The solution preparation was the same as for Formulation I. The spraydrying process conditions were the same when going from Formulation I toFormualtion XXXIII except that the inlet temperature was decreased from180° C. to 100° C., the aspirator rate was changed from 90% to 80% (35cubic meters per hour to 32 cubic meters per hour) and the feed rate wasincreased from 8.6 to 10.2 mL/min, respectively.

TABLE 15 Spray Drying Process Conditions Formulation Process ParametersXVIII XIX XX XXI XXII Liquid feedstock solids 5 3.3 10 10 10concentration (g/L) Process gas inlet 180 180 115 180 180 temperature (°C.) Process gas outlet 61-87 77-92 67-68 89-92 74-75 temperature (° C.)Process gas flowrate 667 667 667 667 667 (liter/hr, LPH) Atomization gas35 35 32 35 29 flowrate (meters³/hr) Liquid feedstock flowrate 6.2 6.22.5 5.9 10 (mL/min) Formulation Process Parameters XXIII XXIV XXV XXVIXXVII Liquid feedstock solids 10 10 10 2 2 concentration (g/L) Processgas inlet 180 100 100 180 180 temperature (° C.) Process gas outlet71-74 55-57 57-59 74-78 77-80 temperature (° C.) Process gas flowrate667 667 667 667 667 (liter/hr, LPH) Atomization gas 29 32 32 29 29flowrate (meters³/hr) Liquid feedstock flowrate 12.1 2.9 2.8 10.2 10.5(mL/min) Formulation Process Parameters XXVIII XXIX XXX XXXI XXXIILiquid feedstock solids 15 10 10 10 10 concentration (g/L) Process gasinlet 100 115 115 115 100 temperature (° C.) Process gas outlet 54-5665-66 64-67 65-66 65-66 temperature (° C.) Process gas flowrate 667 667667 667 667 (liter/hr, LPH) Atomization gas 32 32 32 32 32 flowrate(meters³/hr) Liquid feedstock flowrate 3.2 2.8 2.7 2.7 2.7 (mL/min)

The spray drying process conditions for Formulation XXXIII was: Liquidfeedstock solids concentration was 10 g/L, Process gas inlet temperaturewas 100° C., Process gas outlet temperature was 42-43° C., Process gasflowrate was 667 liters per hour, Atomization gas flowrate (meters3/hr)was 32 cubic meters per hour, and Liquid feedstock flowrate was 10.2mL/min.

B. Powder Characterization.

Powder physical and aerosol properties are summarized in Tables 16 to 20below. Values with ± indicate standard deviation of the value reported.Two-stage ACI-2 results are reported in Table 16 for FPF_(TD)<3.4 μm andFPF_(TD)<5.6 gm. All formulations had a FPF_(TD)<3.4 μm greater than20%, and all but Formulations XXV, XXX and XXXI had a FPF_(TD)<3.4 μmgreater than 30%. Formulations XVIII, XIX, XX, XXI, XXIV, XXVIII, andXXXII each had a FPF_(TD)<3.4 μm greater than 45%. All formulations hada FPF_(TD)<5.6 μm greater than 40%. Formulations XVIII through XXIV,XXVII, XXVIII, XXXII, and XXXIII each had a FPF_(TD)<5.6 μm of greaterthan 60%.

TABLE 16 Aerodynamic properties ACI-2 FPF_(TD) < 3.4 μm FPF_(TD) < 5.6μm Formulation % % XVIII 66.90% ± 0.52% 82.35% ± 3.70% XIX 47.49% ±4.65% 67.70% ± 1.20% XX 53.96% ± 1.44% 73.00% ± 1.80% XXI 48.24% ± 0.49%68.78% ± 1.81% XXII 40.29% ± 0.28% 65.33% ± 0.41% XXIII 37.80% ± 2.97%62.74% ± 2.47% XXIV 53.92% ± 2.25% 69.47% ± 0.21% XXV 29.03% ± 0.12%57.84% ± 0.52% XXVI 39.26% ± 1.35% 59.61% ± 0.90% XXVII 43.06% ± 5.09%65.48% ± 6.09% XXVIII 56.37% ± 1.45% 71.90% ± 0.57% XXIX 33.70% ± 0.68%50.43% ± 4.14% XXX 22.46% ± 0.73% 45.76% ± 1.25% XXXI 24.40% ± 3.68%41.84% ± 4.50% XXXII 60.19% ± 1.59% 78.87% ± 0.66% XXXIII 38.73% ± 2.10%64.87% ± 1.59%

Data for Formulations XVIII and XIX is not available for the datapresented in Tables 16 to 20, except for RODOS data reported forFormulation XVIII in Table 20.

All formulations had a tapped density greater than 0.35 g/cc, and allbut Formulations XXIII and XXIV had a tapped density greater than 0.40g/cc. Formulations XX, XXI, XXII, XXV, XXVI, XXVIII, XXX, XXXI, andXXXII each had a tapped density greater than 0.50 g/cc. Formulation XXIhad a tapped density of 0.80 g/cc. All formulations had a Hausner Ratiogreater than or equal to 1.5. Formulations XXII, XXIII, XXIV, XXVI,XXVII, XXVIII, XXX, XXXI, and XXXIII each had a Hausner Ratios greaterthan 2.0. Formulation XXII had a Hausner Ratio of 3.07. Densitymeasurements for Formulation XXIX was unavailable.

TABLE 17 Density properties Density Bulk Tapped Hausner Formulation g/ccg/cc Ratio XX 0.34 ± 0.01 0.52 ± 0.05 1.54 XXI 0.46 ± 0.1  0.80 ± 0.171.75 XXII 0.17 ± 0   0.52 ± 0.04 3.07 XXIII 0.18 ± 0.01 0.37 ± 0.06 2.09XXIV 0.16 ± 0.02 0.37 ± 0.01 2.28 XXV 0.52 ± 0.01 0.77 ± 0.10 1.50 XXVI0.23 ± 0.00 0.51 ± 0.04 2.21 XXVII 0.15 ± 0.02 0.42 ± 0.01 2.73 XXVIII0.22 ± 0.07 0.53 ± 0.06 2.40 XXX 0.27 ± 0.02 0.70 ± 0.05 2.56 XXXI 0.31± 0.03 0.65 ± 0.05 2.09 XXXII 0.37 ± 0.02 0.67 ± 0.02 1.81 XXXIII 0.22 ±0.01 0.49 ± 0.01 2.26

Table 18 shows that all formulations had geometric diameters (Dv50) ofless than 3.0 um when emitted from a dry powder inhaler at a flowrate of60 LPM. Formulations XX, XXI, XXII, XXIII, XXIV, XXIX, and XXXII hadDv50 of less than 2.0 um at 60 LPM. All formulations, except XXXI, had aDv50 of less than 6.0 um at 15 LPM. Formulations XXI, XXII, XXV, XXVII,XXVIII, XXIX, XXX, XXXII, and XXXIII each had a Dv50 of less than 5.0 umat 15 LPM.

TABLE 18 Geometric Diameters Dispersibility - Spraytec @ 60 LPM @ 15 LPMFormulation Dv50 (μm) GSD Dv50 (μm) GSD XX 1.28 ± 0.08 5.59 ± 0.18 5.85± 0.18 4.04 ± 0.10 XXI 1.33 ± 0.18 5.15 ± 0.13 2.89 ± 0.06 2.78 ± 0.52XXII 1.55 ± 0.07 5.02 ± 0.34 4.23 ± 0.10 3.20 ± 0.25 XXIII 1.70 ± 0.074.47 ± 0.25 5.09 ± 0.20 3.27 ± 0.11 XXIV 1.89 ± 0.15 5.51 ± 0.15 5.65 ±0.08 2.97 ± 0.05 XXV 2.44 ± 0.14 4.87 ± 0.28 4.04 ± 0.55 3.36 ± 0.13XXVI 2.08 ± 0.04 4.85 ± 0.22 5.38 ± 0.09 3.43 ± 0.08 XXVII 2.09 ± 0.154.51 ± 0.35 4.73 ± 0.13 3.16 ± 0.16 XXVIII 2.25 ± 0.12 5.17 ± 0.50 4.56± 0.16 3.00 ± 0.13 XXIX 1.72 ± 0.02 4.04 ± 0.29 3.55 ± 0.21 5.96 ± 0.46XXX 2.77 ± 0.03 3.84 ± 0.24 4.32 ± 0.18 4.31 ± 0.11 XXXI 2.33 ± 0.054.45 ± 0.27 10.12 ± 0.52  5.53 ± 0.40 XXXII 0.99 ± 0.12 5.40 ± 0.17 2.80± 0.10 3.29 ± 0.13 XXXIII 2.52 ± 0.16 4.9 ± 0.4 4.85 ± 0.08 3.07 ± 0.09

Table 19 shows that all formulations had a capsule emitted particle mass(CEPM) of greater than 94% at 60 LPM, and all formulations except forXXV had a CEPM of greater than 96% at 60 LPM. All formulations exceptfor XXI and XXX had a CEPM of greater than 80% at 15 LPM. FormulationsXX, XXII, XXIII, XXIV, XXV, XXVII, XXVIII, XXXII, and XXXIII each had aCEPM of greater than 90% at 15 LPM.

TABLE 19 Dispersibilty properties Dispersibility - CEPM @ 60 LPM @ 15LPM Formulation CEPM CEPM XX 99.33% ± 0.40% 96.92% ± 0.81% XXI 99.96% ±0.00% 79.46% ± 0.11% XXII 97.46% ± 0.14% 95.94% ± 0.55% XXIII 99.47% ±0.14% 97.92% ± 0.41% XXIV 98.96% ± 0.06% 91.28% ± 8.01% XXV 94.58% ±0.66% 94.12% ± 0.83% XXVI 97.79% ± 0.28% 83.17% ± 9.74% XXVII 98.63% ±0.61% 95.15% ± 0.88% XXVIII 98.66% ± 0.25% 95.23% ± 0.40% XXIX 96.46% ±0.46% 85.83% ± 5.73% XXX 96.07% ± 0.47%  74.60% ± 11.85% XXXI 98.63% ±0.19% 62.70% ± 9.68% XXXII 98.21% ± 0.10% 95.53% ± 0.62% XXXIII 100.07%± 2.01%  95.72% ± 0.99%

Table 20 shows that all measured formulations except XXIX had a Dv50 ofless than 3.0 μm when using the RODOS at a 1.0 bar setting; and allmeasured formulations except)00V, XXVIII, XXIX, and XXX had a Dv50 ofless than 2.0 gm. All measured formulations had a RODOS Ratio for 0.5bar/4 bar of less than 1.4, and all measured formulations except forXXII had a RODOS Ratio for 0.5 bar/4 bar of less than 1.3. All measuredformulations had a RODOS Ratio for 1 bar/4 bar of less than or equal toabout 1.1.

TABLE 20 Dispersibilty properties (Geometric diameter using RODOS) RODOS0.5 bar 1.0 bar 4.0 bar Dv50 Dv50 Dv50 0.5/4 1/4 Form. (μm) GSD (μm) GSD(μm) GSD bar bar XVIII 1.93 1.68 1.89 1.76 1.74 1.71 1.11 1.09 XX 1.662.16 1.46 2.06 1.36 1.92 1.22 1.07 XXI 1.91 2.13 1.83 2.24 1.99 2.190.96 1.08 XXII 1.87 1.95 1.48 1.78 1.37 1.78 1.36 1.08 XXIII 1.95 1.961.74 1.93 1.6 1.91 1.22 1.09 XXIV 2.33 2.28 2.10 2.19 1.91 2.12 1.221.10 XXV 1.90 2.10 1.64 1.99 1.68 2.22 1.13 0.98 XXVI 2.09 1.86 1.831.84 1.68 1.80 1.24 1.09 XXVII 2.15 1.84 1.97 1.83 1.78 1.76 1.21 1.11XXVIII 2.56 2.35 2.25 2.30 2.18 2.26 1.17 1.03 XXIX 2.51 2.41 3.67 2.483.36 2.16 0.75 1.09 XXX 2.62 2.35 2.55 2.34 2.42 2.27 1.08 1.05 XXXI1.96 2.24 1.82 2.18 1.78 2.20 1.10 1.02 XXXII 1.61 2.23 1.46 2.20 1.412.15 1.14 1.04 XXXIII 2.15 2.07 1.90 2.05 1.73 2.06 1.24 1.10

Example 6 Efficacy of Dry Powders in an Ovalbumin Mouse Model ofAllergic Asthma

Dry powder formulations comprised of leucine, sodium chloride,fluticasone propionate (FP) and salmeterol xinafoate (SX) were testedfor activity in a mouse model of allergic asthma. A mouse model ofallergic asthma was established using ovalbumin (OVA). In this model,mice are sensitized to OVA over a period of two weeks and subsequentlychallenged via aerosol with OVA, as shown in Schematic 1. This challengeinduces airway inflammation and causes changes in pulmonary function.The principle change in inflammation is an increase in the number ofeosinophils in the lungs. Similar changes in lung inflammation andpulmonary function are observed in humans with asthma.

Balb/c mice were sensitized and challenged to OVA on the days describedabove. Sensitizations were performed by intraperotineal injection of OVAplus Alum. Challenges were performed by whole body exposure to nebulized1% OVA solution for 20 minutes. Mice were treated with the formulationslisted in Table 9 1 hour before OVA challenge, on days 27 through 29 andonce on day 30.

TABLE 21 Dry powders tested in an OVA mouse model of allergic asthma.Capsules Delivered Dry Powder Composition (quantity, fill FormulationGroup (% w/w) weight, size) Placebo-A Control 100% Leucine 3, 30 mg,size 00 XVIII Control 59.1% leucine, 40.9% 1, 90 mg, size 00 sodiumchloride XIX Active 50.0% leucine, 34.5% 1, 90 mg, size 00 sodiumchloride, 13.5% FP, 2.0% SX XIX Active 50.0% leucine, 34.5% 3, 90 mg,size 00 sodium chloride, 13.5% FP, 2.0% SX

Mice were sensitized and challenged with OVA as described andillustrated in Schematic 1, and treated once a day (QD) with aformulation comprised of leucine (50.0%), NaCl (34.5%), FP (13.5%) andSX (2.0%) (Formulation XIX; see Table 21). Treatments were made in awhole body exposure chamber using a capsule based dry powder inhalersystem. Dose was varied by changing the number of capsules used for eachexposure. Doses reported are the exposed dose each mouse inhaled ascalculated based on the measured aerosol concentration sampled from theexposure chamber, the fraction of FP in the powder, the time ofexposure, and the mouse's mass and minute volume. Mouse minute volumewas calculated using a standard equation (Bide et al. (2000) “Allometricrespiration/body mass data for animals to be used for estimates ofinhalation toxicity to young adult humans”, J. Appl. Toxicol.20:273-290). On the final day of the study (day 31), mice wereeuthanized and bronchoalveolar lavages (BAL) were performed. The totalnumber of cells per BAL was determined. In addition, the percentage andtotal number of macrophages, polymorphonuclear cells (neutrophils),lymphocytes, and eosinophils were determined by differential stainingData depicted the mean±SEM of 5 mice per group and are representative oftwo independent experiments. Data were analyzed by one way ANOVA andTukey's multiple comparison test, and asterisk presented in FIGS. 2A and2B represent a p-value of p<0.01.

The data shown in FIGS. 2A and 2B demonstrated that mice treated withdry powder formulations comprised of FP and SX exhibited a significantreduction in total inflammatory cell counts (FIG. 2A) and in eosinophilcounts (FIG. 2B) as compared to both the leucine control (Placebo-A) anda control powder comprised of leucine and sodium chloride (FormulationXVIII). Because FP is a steroid with known anti-inflammatory properties,the effect observed was attributed to the action of FP in the airway. Itis for this reason that the dose in the figures on the x-axis was statedin terms of mg of FP/kg of body weight. The data suggested that drypowder formulations of FP and SX could be made that are small, dense anddispersible, and in which the activity of the active ingredient was notaltered during the spray drying process.

Example 7 Effect of Dry Powders on Inflammation and AirwayHyperreactivity in an Ovalbumin Mouse Model of Allergic Asthma

A mouse model of allergic asthma was established using ovalbumin (OVA).Balb/c mice were sensitized to ovalbumin (OVA) over a period of twoweeks and subsequently challenged via aerosol with OVA as indicated inSchematic 2 below.

Mice were sensitized to and challenged with OVA on the days depicted inSchematic 2 above. Sensitizations were performed by intraperotinealinjection of OVA plus Alum. Challenges were performed by whole bodyexposure to nebulized 1% OVA solution for 20 minutes. Mice were treatedwith a dry powder comprised of 50.0% Leucine 34.5% sodium chloride,13.5% FP and 2.0% SX (Formulation XVIII) or placebo dry powder (100%Leucine, i.e. Placebo-A) dry powders (DP) 1 hour before OVA challenge ondays 27-29 and twice on day 30. Treatments were made in a whole bodyexposure chamber using a capsule based dry powder inhaler system. On thefinal day of the study (day 31), mice were euthanized andbronchoalveolar lavages (BAL) were performed. The total number of cellsper BAL was determined. In addition, the percentage and total number ofmacrophages, polymorphonuclear cells (neutrophils), lymphocytes andeosinophils were determined by differential staining Data depict themean±SEM of 5 mice per group and are representative of two independentexperiments. Data were analyzed by Student's t-test, and asteriskpresented in FIGS. 3A and 3B represent a p-value of p<0.05.

As seen previously (FIGS. 2A and 2B), mice treated with the FP/SX drypowder exhibited a decline in total inflammatory cell counts and asignificant decrease in eosinophil counts compared to those mice treatedwith the leucine dry powder control (FIGS. 3A and 3B).

In addition to changes in inflammation, mice sensitized to andchallenged with OVA exhibit increased airway hyperreactivity. It wasknown from the literature that salmeterol xinafoate (SX) enhancespulmonary function, resulting in lower sRaw values, for animals andhuman beings challenged with methacholine chloride (MCh) in 0.9% sodiumchloride for inhalation. (Schutz, N. (2004), “Prevention ofbronchoconstriction in sensitized guinea pigs: efficacy of commonprophylactic drugs”, Respir Physiol Neurobiol 141(2): 167-178).

Therefore, specific airway resistance (sRaw) was measured in the mice.These measurements were performed on day 30. Baseline sRaw measurementswere taken for 5 minutes before treatment, after which the animalsreceived the appropriate DP treatment. Immediately following DPtreatments, the animals were returned to the plethysmograph andpost-treatment sRaw measurements were then taken. The mice subsequentlyunderwent methacholine (MCh) challenge with escalating concentrations ofMCh delivered via nebulization in a head chamber. Data is presented asthe average sRaw over the 5 minutes following MCh administration. Naïvemice which were not sensitized to and challenged by OVA also underwentPFT and MCh challenge for the sake of comparison.

As shown in FIG. 3C, the FP/SX dry powder reduced sRaw values to nearthose measured in naïve mice after each concentration of MCh challenge.This observation was due to the combined influence of both the reducedairway hyperreactivity as a result of airway inflammation and theinfluence of the long-acting bronchodilator, SX. The data indicated thatnot only can dry powder formulations be made that are small, dense anddispersible, but also that the activity of the spray dried activeingredients was maintained.

Example 8 Effect of a Monovalent Cation-Based Dry Powder of FP/SX(Formulation X) on Inflammation and Airway Hyperreactivity in anOvalbumin Mouse Model of Allergic Asthma

A. Inflammation

Formulation X (30% leucine, 65.4% NaCl, 4.0% fluticasone propionate and0.58% salmeterol xinafoate, w/w on a dry basis) was evaluated in a mousemodel of allergic asthma using ovalbumin (OVA) as an allergen. The modelhas been described and shown schematically in Examples 6 and 7.

In this model, mice were sensitized to OVA over a period of two weeksand subsequently challenged, via a liquid aerosol, with OVA (Example 6).This challenge induced lung inflammation and increased airwayhyperreactivity in response to an airway challenge. The principle changein inflammation was an increase in the number of eosinophils in thelungs. Similar changes in lung inflammation and pulmonary function havebeen observed in humans with asthma.

Balb/c mice were sensitized and challenged to OVA, as per thesensitization protocol described in Example 6. Mice were treated withPlacebo-B dry powder (98% leucine, 2% NaCl, w/w on a dry basis) andFormulation X. Treatments were made in a whole body exposure chamberusing a capsule based dry powder inhaler system. As in Example 7, on thefinal day of the study (day 31), mice were euthanized andbronchoalveolar lavages (BAL) were performed. The total number of cellsper BAL was determined. In addition, the percentage and total number ofeosinophils was determined by differential staining.

The effect of Formulation X on inflammation was assessed. Fluticasonepropionate (FP) is known to reduce eosinophilic cells and totalcellularity in the mouse OVA model. (Riesenfeld, E. P. (2010), “Inhaledsalmeterol and/or fluticasone alters structure/function in a murinemodel of allergic airways disease”, Respiratory Research, 11:22).However, the effect of co-formulating FP with a sodium salt into a drypowder were unknown in the art. Therefore, Formulation X was tested. Theresults for Formulation X are presented in Table 22. These data showthat Formulation X significantly reduced eosinophilic cells and totalcellularity in comparison to Placebo-B (p<0.01 for both eosinophils andtotal cells).

TABLE 22 Formulation X reduces eosinophilic and total cellularinflammation in a murine mode of allergic asthma Placebo-B Formulation Xcells * 10⁶/ml Std Dev cells * 10⁶/ml Std Dev Eosinophils 0.55 0.27 0.110.10 Total cells 1.38 .50 0.49 0.20 (Cellularity)

B. Airway Hyperreactivity

The sensitization of mice with OVA and subsequent challenging of micewith OVA was achieved, as described and shown schematically in Examples6 and 7. In addition to changes in inflammation, mice sensitized to andchallenged with OVA exhibit increased airway hyperreactivity, asmentioned in Example 7, which can be measured as change in airwayresistance following broncho-provocation. Pulmonary function testing wasconducted one hour following treatment on day 30. This involvedmeasuring the specific airway resistance (sRaw) in the mice. sRaw was ameans for assessing pulmonary function. Baseline sRaw measurements weretaken for 5 minutes. The mice subsequently underwent a methacholine(MCh) challenge for assessing pulmonary function with escalatingconcentrations of MCh delivered via nebulization in a head chamber usingdoses of MCh of 0 mg/ml, 50 mg/ml or 100 mg/ml.

The mice were challenged to test their pulmonary function according tothe methods and schematic described in Example 7. It was known from theliterature that salmeterol xinafoate (SX) enhances pulmonary function,resulting in lower sRaw values, for animals and human beings challengedwith methacholine chloride (MCh) in 0.9% sodium chloride for inhalation.(Schutz, N. (2004), “Prevention of bronchoconstriction in sensitizedguinea pigs: efficacy of common prophylactic drugs”, Respir PhysiolNeurobiol 141(2): 167-178),

While the effects of SX on sRaw were known from the literature, theeffect of co-formulating SX formulations with a sodium salt wereunknown. Formulation X (30% leucine, 65.4% NaCl, 4.0% fluticasonepropionate and 0.58% salmeterol xinafoate, w/w on a dry basis) wastested, and compared to Placebo-B dry powder (98% leucine, 2% NaCl, w/won a dry basis). Results from pulmonary function testing are shown inFIG. 4. These data show that Formulation X significantly reduced sRawduring MCh challenge compared to Placebo-B (p<0.05).

Example 9 Effect of a Monovalent Cation-Based Dry Powder of TiotropiumBromide (Formulation XX) on Airway Hyperreactivity in an Ovalbumin MouseModel of Allergic Asthma

A similar ovalbumin mouse model of allergic asthma as was used inExamples 6 to 8. The protocol of Examples 6 and 7 of sensitization andsubsequent challenging with OVA was followed. Pulmonary function testingwas conducted as per Example 8.

It was known from the literature that tiotropium bromide (TioB) enhancespulmonary function, resulting in lower sRaw values, for animals andhuman beings challenged with methacholine chloride (MCh) in 0.9% sodiumchloride for inhalation. (Ohta, S. et al. (2010), “Effect of tiotropiumbromide on airway inflammation and remodeling in a mouse model ofasthma”, Clinical and Experimental Allergy 40:1266-1275).

While the effects of TioB on sRaw were known from the literature, theeffect of co-formulating the TioB formulation with a sodium salt wasunknown. Formulations XX (34.47% leucine, 65.42% NaCl and 0.113%tiotropium bromide, w/w on a dry basis) was tested, and compared toPlacebo-B dry powder (98% leucine, 2% NaCl, w/w on a dry basis). Resultsfrom pulmonary function testing are shown in FIG. 5. These data showthat Formulation XX significantly reduced sRaw during MCh challengecompared to Placebo-B (p<0.00001).

Example 10 Efficacy of Monovalent Cation-Based Dry Powders ContainingFP/SX in a Mouse House Dust Mite Model of Allergic Asthma

Dry powder (DP) formulations comprised of leucine, sodium chloride,fluticasone propionate (FP) and salmeterol xinafoate (SX) were furthertested for an ability to reduce inflammation and airway hyperreactivityin a mouse house dust mite (HDM) model of allergic asthma. A mouse modelof allergic asthma was established by intranasal administration of 25 μgof freeze-dried Dermatophagoides pteronyssinus HDM on days 0, 7 and 14over a two week period as shown in the Schematic 3 below. Exposure ofHDM to mice has been shown to cause an increase in total inflammatorycells, primarily eosinophils, in their lungs and, with chronic exposure,airway hyperreactivity. These similar changes in lung inflammation andpulmonary function have been observed in human asthma.

Balb/c mice were treated with a dry powder comprised of 50.0% Leucine,34.5% sodium chloride, 13.5% FP and 2.0% SX (Formulation XIX) or aplacebo dry powder of 100% Leucine, on a dry basis (Placebo-A) once perday (QD), starting with the final day of HDM sensitization (day 14)until day 17. Treatments were made in a whole body exposure chamberusing a capsule-based dry powder inhaler system. Immediately followingtreatment on day 17, the animals underwent pulmonary function testing(PFT) by dual chamber plethysmography. Specific airway resistance (sRaw)measurements were taken at baseline and following methacholine (MCh)challenge. Immediately following dry powder treatment, 5 minutes ofbaseline sRaw measurements were taken. sRaw measurements were then takenfollowing escalating doses of MCh delivered via nebulization to the headchamber. Data is presented as the average sRaw over the 5 minutesfollowing MCh administration.

Mice were then euthanized and bronchoalveolar lavages (BAL) wereperformed. The total number of cells per BAL was determined, and thepercentage and total number of macrophages, polymorphonuclear cells(neutrophils), lymphocytes, and eosinophils were determined bydifferential staining A group of naïve, non-sensitized, untreated micealso underwent PFT and BAL for comparison. Data depict the mean±SEM andwere analyzed by one way ANOVA and Tukey's multiple comparison test(*p<0.5) (**p<0.01).

The FP/SX dry powder significantly reduced total inflammatory cellcounts to near that of naïve mice in comparison to leucine placebotreatment (FIG. 6A). In addition, eosinophil counts were significantlyreduced by nearly 60% (FIG. 6B). The reduction in inflammatory andeosinophil counts indicated that the anti-inflammatory properties of theFP steroid were maintained in the dry powder.

Furthermore, the FP/SX dry powder reduced sRaw values below thosemeasured in both HDM sensitized mice that received placebo dry powdertreatment (FIG. 6C). The fact that mice treated with the FP/SX drypowder demonstrated less of a bronchoconstrictive response to MCh thannaïve mice, while exhibiting increased eosinophilia suggested that thereduced hyperreactivity in mice treated with the FP/SX dry powder wasdue primarily to the influence of the long-acting bronchodilator SX.Thus, the data indicated that activity of each active ingredient in asmall, dense and dispersible dry powder formulation described herein wasretained.

Example 11 Efficacy of Monovalent Cation-Based Dry Powders ContainingFP/SX in an LPS Mouse Model of Acute Lung Injury

In this study, a mouse model of acute lung injury was used to study theeffects of FP/SX co-formulated with a sodium salt on pulmonaryinflammation. Mice were exposed to aerosolized lipopolysaccharide (LPS)isolated from Pseudomonas aeruginosa. This challenge resulted in lunginflammation and caused changes in pulmonary function. The principlechange in inflammation was an increase in the number of neutrophils inthe lungs. Similar changes in lung inflammation and pulmonary functionhave been observed in humans suffering from acute lung injury.

Mice were exposed to whole body exposure with nebulized LPS, 1.12 mg/ml,for 30 minutes. Treatment with dry powder Formulation X (30% leucine,65.4% NaCl, 4.0% fluticasone propionate and 0.58% salmeterol xinafoate,w/w on a dry basis) was performed 1 hour following LPS exposure using awhole body exposure chamber using a capsule based dry powder inhalersystem. Animals were treated with two, 90 mg capsules. A separate groupof animals was treated with two, 30 mg capsules of Placebo-B dry powder(98% leucine, 2% NaCl, w/w on a dry basis). Three hours following drypowder treatment, all mice were euthanized and underwent whole lunglavage for determination of total and differential cell counts.

As shown in Table 23, treatment of mice with Formulation X significantlyreduced total cell counts (p<0.01) and neutrophils (p<0.01) in the BALfluid when compared with animals exposed to Placebo-B. Thus, treatmentof mice with Formulation X significantly reduced lung inflammation in anLPS model of acute lung injury.

TABLE 23 Formulation X reduces inflammation in a rodent model of acutelung injury. Placebo-B Formulation X cells * 10⁶/ml Std Dev cells *10⁶/ml Std Dev Neutrophils 0.81 0.23 0.36 0.12 Total cells 0.98 0.190.55 0.15 (Cellularity)

Example 12 Efficacy of Monovalent Cation-Based Dry Powder ContainingCiprofloxacin in a Mouse Model of Bacterial Pneumonia

A neutropenic mouse model of Pseudomonas aeruginosa was used to evaluatethe efficacy of Formulation IV (10.0% mannitol, 40% sodium chloride, 50%ciprofloxacin hydrochloride, w/w on a dry basis). Mice (C57BL6; ˜20 g)were given two doses of cyclophosphamide monohydrate (Sigma Aldrich; StLouis, Mo.) dissolved in sterile water for injection on day −4 (200mg/kg) and day −1 (100 mg/kg) relative to the day of infection (day 0).Cyclophosphamide was given by intraperotineal injection and acts todeplete neutrophils.

P. aeruginosa (PAO1) was prepared by growing a culture in 2.0 mL ofLuria Bertani (LB) broth overnight at 37° C. with shaker speed of 430rpm. Cultures were diluted 1:100 the following day and grown to anOD₆₀₀˜0.3. Once the OD₆₀₀ reached ˜0.3, three washes were performed insterile PBS and the resulting suspension was subsequently diluted 1:2000in sterile PBS [˜1.3×10⁵ Colony forming units (CFU)/mL]. Mice wereinfected with 50 μL of bacterial suspension (˜6×10³ CFU/mouse) byintranasal instillation while under injectable anesthesia.

Mice were exposed to Formulation IV or a control powder comprised of100% leucine on a dry basis (Placebo-A) as a control in a whole-bodyexposure system using a capsule based system and a flow control unitconnected to a pie chamber cage that individually holds up to 11animals. Treatments were performed 4 hours after infection with P.aeruginosa. Exposure times were dependent on the number of capsules tobe emitted. Doses reported are the exposed dose each mouse inhaled ascalculated based on the measured aerosol concentration sampled from theexposure chamber, the fraction of ciprofloxacin in the powder, the timeof exposure, and the mouse's mass and minute volume. Mouse minute volumewas calculated using a standard equation (Bide et al. (2000) “Allometricrespiration/body mass data for animals to be used for estimates ofinhalation toxicity to young adult humans”, J. Appl. Toxicol.20:273-290). Twenty-four hours after infection, mice were euthanized bypentobarbital injection and lungs were collected and homogenized insterile PBS. Lung homogenate samples were serially diluted in sterilePBS and plated on TSA blood agar plates. CFU were enumerated on thefollowing day.As shown in FIG. 7, compared to control animals exposed toPlacebo-A, Formulation IV-treated animals exhibited greatly reducedbacterial titers 24 hours after infection. This data suggested thatspray-dried ciprofloxacin was active against P. aeruginosa at doses ofless than 7.5 mg/kg and that spray-dried DP formulations ofciprofloxacin could be made small, dense and dispersible.

Example 13 Efficacy of Monovalent Cation-Based Dry Powder ContainingLevofloxacin in a Mouse Model of Bacterial Pneumonia

A mouse model of bacterial infection was used to evaluate the efficacyof Formulation XXI in vivo. Neutropenia was induced by injection ofcyclophosphamide (100 mg/kg) on days −4 and −1. Bacteria (Pseudomonasaeruginosa) were grown overnight in 2 ml of Luria Bertani broth at 37°C. and approximately 5×10³ CFU were delivered per mouse via intranasaladministration in 50 μl of PBS. Four hours following infection theanimals were treated with Formulation XXI (27% leucine, 53% NaCl and 20%levofloxacin, w/w on a dry basis) and with Placebo-B dry powder (98%leucine, 2% NaCl) using a whole body exposure chamber and a capsulebased dry powder inhaler system. The next day, animals were euthanizedand the lungs and the spleen were harvested and homogenized to determinelung bacterial load and systemic bacterial load, respectively.Homogenates were serially diluted on tryptin-soyagar plates and allowedto incubate overnight at 37° C. The following day, colony forming units(CFU) were counted and CFU/ml for each the lung and the spleen wascalculated.

Levofloxacin, being a potent antibiotic would be expected tosignificantly reduce CFU count in the spleen when administered throughthe gastro-intestinal tract. What was unknown were the following: (i)would co-formulating levofloxacin with a sodium salt have any effect onthe efficacy of levofloxacin when administered to the lungs, and (ii)would these co-formulation of levofloxacin, when administered to thelungs, cause a reduction of CFU count in the spleen. The results areshown in Table 24. It was seen that Formulation XXI significantlyreduced bacterial burden in the lung by more than 4 log₁₀ CFU and in thespleen by almost 100-fold compared to Placebo-B treated animals. Thus,treatment of mice with Formulation XXI significantly reduced lung andsystemic bacterial burden (CFU count) during Pseudomonas aeruginosainfection, proving that levofloxacin could be (i) co-formulated with asodium salt and still have efficacy when administered to the lungs, and(ii) administered to the lungs as a co-formulation to reduce CFU countin the spleen.

It was observed from these data that the presence of sodium inlevofloxacin dry powder formulations did not have a deleterious effecton the efficacy of levofloxacin. This is a surprising result given theliterature which says that various salt formulations deleteriouslyaffect the bioavailability of levofloxacin taken through thegastrointestinal tract. (Flor, S. et al. (1990), “Effects ofMagnesium-Aluminum Hydroxide and Calcium Carbonate Antacids onBioavailability of Ofloxacin”, Antimicrobial Agents and Chemotherapy34(12): 2436-2438), and (Pai, M P. et al. (2006), “Altered steady statepharmacokinetics of levofloxacin in adult cystic fibrosis patientsreceiving calcium carbonate”, J. Cyst. Fibros., August; 5(3):153-7).(Ofloxacin is a racemic mixture, which consists of 50% levofloxacin,which is known to be biologically active, and 50% of its enantiomer.)

TABLE 24 Formulation XXI reduces bacterial burden during Pseudomonasaeruginosa infection Placebo-B Formulation XXI CFU/ml Std Dev CFU/ml StdDev Lung 2.85 × 10⁸ 2.88 × 10⁸ 2.08 × 10⁴ 3.87 × 10⁴ Spleen 1.57 × 10⁵1.78 × 10⁵ 2.16 × 10³ 6.81 × 10²

Example 14 Efficacy of Monovalent Cation-Based Dry Powders ContainingInsulin in Reducing Blood Glucose Levels in a Mouse Model

In this study, Formulations XXIV and XXVIII (Table 25) containingrecombinant human insulin (Sigma-Aldrich, St. Louis, Mo., approx. 27.5U/mg, dry powder) were used to determine if monovalent cation-based drypowder formulations could be used to deliver proteins to the lung and ifthis dry powder could be used to deliver proteins systemically.

TABLE 25 Insulin containing dry powder formulations % % % % SaltExcipient Drug HCl load load load load Form. Salt (w/w) Excipient (w/w)Drug (w/w) (w/w) XXIV Sodium 49.0 Mannitol 39.0 Insulin 8.0 4.0 sulfateXXVIII Sodium 54.0 Mannitol 39.0 Insulin 5.0 2.0 sulfate

The sodium sulfate/mannitol solution was adjusted with hydrochloric acid(HCl) to obtain a low pH solution in which the insulin was soluble. Theresulting DP contained 8% insulin (Formulation XXIV) and 5% insulin(Formulation XXVIII).

In this study, mice (n=5) were treated with 6 capsules of eitherFormulation XXIV or XXVIII, with another group of animals that weretreated with 6 capsules of Placebo-B control powder (98% leucine, 2%NaCl), using a whole body exposure chamber with a capsule based drypowder inhaler system. Whole blood was drawn from the mice by tail snip.Blood glucose levels were measured at 0 minutes (immediately before DPtreatment), 30 minutes, 1 hour and 2 hours following DP treatment usinga LIFESCAN OneTouch Ultra 2 blood glucose monitoring system (Johnson &Johnson, New Brunswick, N.J.).

The results are shown in FIG. 8 (Formulation XXIV, 8% insulin) and FIG.9 (Formulation XXVIII, 5% insulin). The placebo treated animals,Placebo-B, showed a small increase in glucose levels, likely as a stress(“fight or flight”) response to the powder administration and/or tailsnip for the blood measurement. Glucose levels rapidly and significantlydropped in insulin-treated animals with levels reaching the lowerdetection limit of the glucose sensor (20 mg/dL) at 2 hours after DPtreatment. This demonstrated that monovalent cation-containing drypowders can be utilized to deliver proteins. Hormones, such as insulin,delivered in an animal model by DP can have fast-acting, systemicphysiological, pharmacological effects in vivo.

Example 15 Sodium Formulation of an Immunoglobulin Protein Provides forDelivery of the Protein Both Locally in the Lungs and Systemically

In this study, Formulation XXV (50.0% sodium sulfate, 47.5% mannitol,2.5% bovine immunoglobulin G (IgG), w/w on a dry basis) was used todetermine if monovalent cation salt-based dry powder formulations couldbe used to deliver proteins to the lungs and/or systemically by way ofthe lungs.

In this study, mice were treated with Formulation XXV using a whole bodyexposure chamber using a capsule-based dry powder inhaler system.Animals were then treated with 3 or 6 capsules of Formulation XXV withanother group of animals that were treated with 6 capsules of placebocontrol powder (98% leucine, 2% NaCl; Placebo-B). The placebo controlswere run to ensure that there was no cross reactivity with the bovineIgG assay and native mouse proteins in either the serum or thebroncho-alveolar lavage (BAL). Immediately following DP treatment theanimals were euthanized, underwent BAL and serum was collected. Lavagefluid and serum were then assayed for bovine IgG using a commerciallyavailable ELISA kit.

The data for lung detection of the IgG are shown in FIG. 10-A and forserum detection of the IgG are shown in FIG. 10-B. Placebo-B (n=3animals) was below the detectable range of the assay, which wasindicative that there was no cross reactivity between the bovine IgG andthe native mouse protein in either the serum or the BAL. It could beseen that detectable IgG delivered to the lung, and systemically by wayof the lungs, increased stepwise with increasing number of capsulesdelivered to the animals. This demonstrated that monovalentcation-containing dry powders can be utilized to deliver proteins. Evenlarge proteins such as immunoglobulins, such as IgG, and antibodiesdelivered in an animal model by DP could have fast acting, systemicphysiological, pharmacological effects in vivo.

Example 16 Optimization of a Dry Powder Sodium-Based Formulation ofFluticasone Propionate and Salmeterol Xinafoate

Two sodium salt-based fluticasone propionate/salmeterol xinafoate(FP/SX) formulations were processed, Formulations I and XXXIII. (SeeTable 26) Formulation I dry powder was produced by spray drying on theBüchi B-290 Mini Spray Dryer (BÜCHI Labortechnik AG, Flawil,Switzerland) with powder collection in a 60 mL glass vessel from a HighPerformance cyclone. The system used the Büchi B-296 dehumidifier and anexternal LG dehumidifier (model 49007903, LG Electronics, EnglewoodCliffs, N.J.) was run constantly. Atomization of the liquid feedutilized a Büchi two-fluid nozzle with a 1.5 mm diameter. The two-fluidatomizing gas was set at 40 mm and the aspirator rate to 90% (35 m³/h).Room air was used as the drying gas. Inlet temperature of the processgas was 180° C. and outlet temperature from 86° C. to 87° C. with aliquid feedstock flow rate of 8 mL/min to 9 mL/min. The solidsconcentration was 10 g/L in 60% ethanol and 40% water.

Formulation XXXIII shared the same chemical components and compositionas Formulation I, as listed in Table 26. The solution preparation wasthe same as for Formulation I, namely that the solids concentration was10 g/L in 60% ethanol and 40% water. The spray drying process conditionsof Formulation XXXIII were the same as for Formulation I, except thatfor Formulation XXXIII, the inlet temperature was decreased from 180° C.to 100° C., the aspirator rate was changed from 90% to 80% (35 cubicmeters per hour to 32 cubic meters per hour), and the feed rate wasincreased from 8.6 to 10.2 mL/min.

TABLE 26 Sodium chloride-based formulations of FP/SX % % % SaltExcipient Drug load load load Formulation Salt (w/w) Excipient (w/w)Drug (w/w) I Sodium 65.4 Leucine 30.0 FP/SX 4.0/0.58 chloride XXXIIISodium 65.4 Leucine 30.0 FP/SX 4.0/0.58 chloride

The modified processing conditions used to generate Formulation XXXIIIwere determined through process optimization. Formulation XXXIII had asignificantly higher capsule emitted powder mass (CEPM), both at ahigher flow rate of 60 LPM and at a lower flow rate of 15 LPM thatFormulation I had at 60 LPM and 30 LPM. It should be noted thatFormulation I was only run at a lower flow rate of 30 LPM, whichprovides more dispersion energy than at 15 LPM, yet Formulation XXXIIIhad a significantly higher CEPM than Formulation I at the lower flowrates. CEPM is relevant when it comes to determining the dose of theformulation and therefore the active agent a patient would receive fromthe inhaler. Formulation XXXIII also has an improved ratio of CEPM highflow rate/CEPM low flow rate that Formulation I. Results from the CEPMcharacterization can be seen in Table 27.

This example showed how a monovalent salt formulation which contained anactive agent could be optimized to produce particles and powders withimproved properties.

TABLE 27 CEPM Dispersibilty Properties Dispersibility - CEPM FormulationI @ 30 LPM Formulation @ 60 LPM Formulation II @ 15 LPM I   62% ± n/a  44% ± n/a XXXIII 100.1% ± 2.0% 95.7% ± 1.0% n/a = not available

Example 17 A Monovalent Metal Cation DP Containing Tiotropium Bromide isEffective to Enhance Pulmonary Function in Mice Challenged withMethacholine Chloride (MCh) in a Mouse Model of Rhinovirus Infection

A mouse model of Rhinovirus infection with Rhinovirus minor 1B strainwas used (REF). Female inbred Balb/c mice (body weights on initial dayof use: 16.8-24.3 g) were obtained from Charles River Laboratories. Mice(n=4) were infected intranasally with 5×10⁶ TCID50 of Rhinovirus-1B.Mice were exposed to dry powder Formulation XXXII using a customdesigned whole body exposure system 18 hours after virus infection.Pulmonary function testing was conducted at approximately 1 hourfollowing dry powder treatment. Baseline specific airway resistance(sRaw) measurements were taken for 5 minutes before treatment and themice subsequently underwent methacholine (MCh) challenge with escalatingconcentrations of MCh (0-100 mg/ml) delivered via nebulization into thehead chamber. Data in Table 28 is presented as the average sRaw over the5 minutes following MCh administration.

TABLE 28 MCh Placebo-B Formulation XXXII Concentration sRaw sRaw (mg/ml)(cmH₂O * s) Std Dev (cmH₂O * s) Std Dev 0 3.30 0.22 2.71 (n.s.) 0.96 508.55 3.92 2.68 (p < 0.05) 1.04 100 15.26 4.81 3.47 (p < 0.01) 0.50

The data show that Formulation XXXII significantly reduced sRaw duringMCh challenge compared to Placebo (p<0.05) at 50 and 100 mg/ml MCh.

The content of each of the patents, patent applications, patentpublications and published articles cited in this specification areherein incorporated by reference in their entirety.

What is claimed is:
 1. A respirable dry powder comprising respirable dryparticles that comprise a) one or more monovalent metal cation salts;wherein the one or more monovalent metal cation salts is present in anamount of at least about 3% by weight of the dry particle, and b) apharmaceutically active agent; wherein the pharmaceutically active agents an antibiotic, a LABA, a LAMA, a corticosteroid, or any combinationthereof. and wherein the respirable dry particles have a volume mediangeometric diameter (VMGD) of about 10 microns or less and adispersibility ratio (1 bar/4 bar) of less than about 1.5 as measured bylaser diffraction (RODOS/HELOS system), and wherein the respirable dryparticles have a tap density between 0.45 g/cc and 1.2 g/cc, with theproviso that the respirable dry particles do not contain a divalentmetal cation in an amount of 3% or more by weight of the dry particle.2. The respirable dry powder of claim 1, with the further proviso thatthe respirable dry particles do not contain a divalent metal cation saltin an amount of 5% or more by weight of the dry particle.
 3. Therespirable dry powder of claim 1, wherein the respirable dry particleshave a volume median geometric diameter (VMGD) of about 5.0 microns orless.
 4. (canceled)
 5. The respirable dry powder of claim 1, wherein therespirable dry powder has a Fine Particle Fraction (FPF) of less than5.6 microns of at least 45%. 6.-7. (canceled)
 8. The respirable drypowder of claim 1, wherein the respirable dry powder have a mass medianaerodynamic diameter (MMAD) of about 5 microns or less. 9.-10.(canceled)
 11. The respirable dry powder of claim 1, wherein therespirable dry powder further comprises at least one pharmaceuticallyacceptable excipient. 12.-13. (canceled)
 14. The respirable dry powderof claim 11 wherein the at least one excipient is selected from thegroup consisting of leucine, maltodextrin, mannitol and combinationsthereof.
 15. (canceled)
 16. The respirable dry powder of claim 1,wherein the monovalent metal cation salt is a sodium salt.
 17. Therespirable dry powder of claim 16, wherein the sodium salt is sodiumchloride, sodium lactate, sodium citrate, sodium sulfate or combinationsthereof.
 18. The respirable dry powder of claim 1, wherein themonovalent metal cation salt is a potassium salt. 19.-21. (canceled) 22.The respirable dry powder of claim 1, wherein the tap density of thepowder is greater than 0.55 g/cc. 23.-25. (canceled)
 26. A respirabledry powder comprising respirable dry particles that comprise a) one ormore monovalent metal cation salts; wherein the one or more monovalentmetal cation salts is present in an amount of at least about 3% byweight of the dry particle, and b) a pharmaceutically active agent;wherein the pharmaceutically active agent is a macromolecule, andwherein the respirable dry particles have a volume median geometricdiameter (VMGD) of about 10 microns or less and a dispersibility ratio(1 bar/4 bar) of less than about 1.5 as measured by laser diffraction(RODOS/HELOS system), and wherein the respirable dry particles have atap density between 0.45 g/cc and 1.2 g/cc, with the proviso that therespirable dry particles do not contain a divalent metal cation in anamount of 3% or more by weight of the dry particle.
 27. The respirabledry powder of claim 26, wherein the pharmaceutically active agent isselected from the group consisting of an antibody, a hormone, and agrowth factor. 28.-56. (canceled)
 57. A method for treating arespiratory disease comprising administering to the respiratory tract ofa patient in need thereof an effective amount of a respirable dry powderof claim
 1. 58. A method for treating or preventing an acuteexacerbation of a respiratory disease comprising administering to therespiratory tract of a patient in need thereof an effective amount of arespirable dry powder of claim
 1. 59. A method for treating orpreventing an infectious disease of the respiratory tract comprisingadministering to the respiratory tract of a patient in need thereof aneffective amount of a respirable dry powder of claim
 1. 60.-63.(canceled)
 64. The method of claim 57, where the respiratory disease isasthma, airway hyperresponsiveness, seasonal allergic allergy,bronchiectasis, chronic bronchitis, emphysema, chronic obstructivepulmonary disease, or cystic fibrosis.
 65. A respirable dry powdercomprising respirable dry particles that comprise a) one or moremonovalent metal cation salts; wherein the one or more monovalent metalcation salts is present in an amount of at least about 3% by weight ofthe dry particle, and b) a pharmaceutically active agent; wherein thepharmaceutically active agent is a MABA, and wherein the respirable dryparticles have a volume median geometric diameter (VMGD) of about 10microns or less and a dispersibility ratio (1 bar/4 bar) of less thanabout 1.5 as measured by laser diffraction (RODOS/HELOS system), andwherein the respirable dry particles have a tap density of greater thanabout 0.45 g/cc, with the proviso that the respirable dry particles donot contain a divalent metal cation in an amount of 3% or more by weightof the dry particle.
 66. The respirable dry powder of claim 1, whereinthe respirable dry particles are further characterized by a capsuleemitted powder mass (CEPM) of at least 80% when emitted from a passivedry powder inhaler under the following conditions: a total inhalationenergy of less than about 2 Joules using a size 3 capsule that is atleast 10% full with the respirable dry particles.
 67. The respirable drypowder of claim 1, wherein the respirable dry particles are furthercharacterized a geometric size (Dv50) of less than 5 micrometers whenemitted from a passive dry powder inhaler that has a resistance of about0.036 sqrt(kPa)/liters per minute (LPM) under the following conditions:a total inhalation energy of less than about 1.2 Joules at a flow rateof 30 LPM using a size 3 capsule that contains a total mass of 20 mg,said total mass consisting of the respirable dry particles.